Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs

ABSTRACT

Embodiments of the present invention provide a method for treatment of respiratory disorders such as asthma, chronic obstructive pulmonary disease, and chronic sinusitis, including cystic fibrosis, interstitial fibrosis, chronic bronchitis, emphysema, bronchopulmonary dysplasia and neoplasia. The method involves administration, preferably oral, nasal or pulmonary administration, of anti-inflammatory and anti-proliferative drugs (rapamycin or paclitaxel and their analogues) and an additive.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/903,379, filed May 28, 2013, which is a continuation of U.S.application Ser. No. 12/135,648, filed Jun. 9, 2008, which is acontinuation-in-part of application Ser. No. 11/942,459, filed Nov. 19,2007, which claims the benefit of priority of U.S. ProvisionalApplication No. 60/860,084, filed on Nov. 20, 2006, U.S. ProvisionalApplication No. 60/880,742, filed Jan. 17, 2007, U.S. ProvisionalApplication No. 60/897,427, filed on Jan. 25, 2007, U.S. ProvisionalApplication No. 60/903,529 filed on Feb. 26, 2007, U.S. ProvisionalApplication No. 60/904,473 filed Mar. 2, 2007, U.S. ProvisionalApplication No. 60/926,850 filed Apr. 30, 2007, U.S. ProvisionalApplication No. 60/981,380 filed Oct. 19, 2007, and U.S. ProvisionalApplication 60/981,384 filed Oct. 19, 2007, the disclosures of all ofwhich are incorporated by reference herein.

FIELD OF THE INVENTION

Embodiments of the present invention relate to a method for treatment ofrespiratory disorders such as asthma and chronic obstructive pulmonarydisease, including cystic fibrosis, interstitial fibrosis, chronicbronchitis, emphysema, bronchopulmonary dysplasia and neoplasia. Themethod involves administration, preferably oral, nasal or pulmonaryadministration, of anti-inflammatory and anti-proliferate drugs(rapamycin or paclitaxel and their analogues).

BACKGROUND OF THE INVENTION

Chronic obstructive pulmonary disease (COPD) is a term used to classifytwo major airflow obstruction disorders: chronic bronchitis andemphysema. Approximately 16 million Americans have COPD, 80-90% of themwere smokers throughout much of their lives. COPD is a leading cause ofdeath in the U.S., accounting for 122,283 deaths in 2003. The cost tothe USA for COPD was approximately $20.9 billion in direct health careexpenditures in 2003. Chronic bronchitis is inflammation of thebronchial airways. The bronchial airways connect the trachea with thelungs. When inflamed, the bronchial tubes secrete mucus, causing achronic cough. Emphysema is an overinflation of the alveoli, or air sacsin the lungs. This condition causes shortness of breath.

In emphysema, the alveolar sacs are overinflated as a result of damageto the elastin skeleton of the lung. Inflammatory cells in emphysematouslung release elastase enzymes, which degrade or damage elastin fiberswithin the lung matrix. Emphysema has a number of causes, includingsmoking, exposure to environmental pollutants, alpha-one antitrypsindeficiency, and aging.

There are no therapies available today to halt the progression of COPD.Inhaled steroids have recently been studied (Lung Health Study II) as apotential therapy to prevent loss of lung function in emphysemapatients. The study concluded, however, that inhaled steroids failed toalter the decline in lung function over time. As patients lose lungfunction over time, they may become dependent on oxygen, and eventuallyend up on ventilators to assist with respiration. A relatively newtreatment for patients with emphysema is lung volume reduction surgery.Emphysema patients suffer from air trapping in the lungs. This flattensthe diaphragm, impairing the ability to inhale and exhale. Patients withemphysema localized to the upper lung lobes are candidates for lungvolume reduction surgery, where the upper lobes are surgically removedto restore the natural concavity and function of the diaphragm.

Acute exacerbation of asthma is often caused by spasm of the airways, orbronchoconstriction, causing symptoms including sudden shortness ofbreath, wheezing, and cough. Bronchospasm is treated with inhaledbronchodilators (anticholinergics such as ipratropium and beta-agonistssuch as albuterol). Patients inhale these medications into their lungsas a mist, produced by either a nebulizer or a hand-held meter dose(MDI) or dry powder (DPI) inhaler. Patients with acute episodes may alsobe treated with oral or intravenous steroids that serve to reduce theinflammatory response that exacerbates the condition.

Asthma is a chronic respiratory disease characterized by inflammation ofthe airways, excess mucus production and airway hyper responsiveness,and a condition in which airways narrow excessively or too easilyrespond to a stimulus. Asthma episodes or attacks cause narrowing of theairways, which make breathing difficult. Asthma attacks can have asignificant impact on a patient's life, limiting participation in manyactivities. In severe cases, asthma attacks can be life threatening.Presently, there is no known cure for asthma.

According to the American Lung Association, there are approximately 20million Americans with asthma in 2002. Fourteen million of them wereadults. Asthma resulted in approximately 1.9 million emergency roomvisits in 2002. The estimated direct cost of asthma in the U.S. is $11.5billion, which is spent on asthma medications, physician office visits,emergency room visits and hospitalizations.

The causes of coronary heart disease and asthma are neointimalproliferation of smooth muscle in arterial vessels and in walls ofairways. One aspect of the invention is to deliver paclitaxel orrapamycin and their analogues to the wall of airways to treat the asthmaand COPD. Drug coated stents with these drugs have been approved forinhibiting the growth of the smooth muscle cells in vascular arterialvessels.

Chronic sinusitis is an inflammation of the membrane lining of one ormore paranasal sinuses. Chronic sinusitis lasts longer than three weeksand often continues for months. In cases of chronic sinusitis, there isusually tissue damage. According to the Center for Disease Control(CDC), thirty seven million cases of chronic sinusitis are reportedannually.

Chronic sinusitis is often difficult to treat successfully, however, assome symptoms persist even after prolonged courses of antibiotics.Steroid nasal sprays and prescribed steroids are commonly used to treatinflammation in chronic sinusitis. When medical treatment fails, surgerymay be the only alternative in treating chronic sinusitis. Presently,the most common surgery done is functional endoscopic sinus surgery, inwhich the diseased and thickened tissues from the sinuses are removed toallow drainage. However, there is a need for better medicine for chronicsinusitis.

The present invention provides a new method for treatment of respiratorydisorders such as asthma, chronic obstructive pulmonary disease, andchronic sinusitis. The method involves administration, preferably oral,nasal or pulmonary administration, of anti-inflammatory andanti-proliferate drugs (rapamycin or paclitaxel and their analogues) andan additive. Embodiments of the present invention provide apharmaceutical formulation comprising a drug for treatment of therespiratory system, and an additive that enhances absorption of the druginto tissue of body passages.

SUMMARY OF THE INVENTION

Embodiments of the present invention are directed to the treatment ofrespiratory disorders by intratracheal administration of an effectiveamount of anti-inflammatory and anti-proliferate drugs (rapamycin orpaclitaxel and their analogues). Respiratory disorders such as asthma,chronic obstructive pulmonary disease, and chronic sinusitis includecystic fibrosis, interstitial fibrosis, chronic bronchitis, emphysema,nasal and sinus dysplasia, bronchopulmonary dysplasia and neoplasia. Thetreatment is intended for a variety of animals, such as prematureneonates to adult humans. Administration of rapamycin or paclitaxel maybe performed by aerosol, which can be generated by a nebulizer, byinhalation or by instillation. The rapamycin or paclitaxel may beadministered alone or with an additive carrier in solution such assaline solution, DMSO, alcohol, or water. It may also be used ascombinations with inhaled bronchodilators (anticholinergics such asipratropium and beta-agonists such as albuterol) and oral or intravenoussteroids. Patients inhale these medications into their lungs as a mist,produced by either a nebulizer or a hand-held meter dose (MDI) or drypowder (DPI) inhaler.

The additive has a hydrophilic part and a drug affinity part. The drugaffinity part is a hydrophobic part and/or has an affinity to thetherapeutic agent by hydrogen bonding and/or van der Waals interactions.The drug affinity part may include aliphatic and aromatic organichydrocarbon compounds, such as benzene, toluene, and alkanes, amongothers. These parts are not water soluble. They have no covalentlybonded iodine. The hydrophilic part may include hydroxyl groups, aminegroups, amide groups, carbonyl groups, carboxylic acid and anhydrides,ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, aminoacid, amino alcohol, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic salts and their substituted molecules,among others. These parts can dissolve in water and polar solvents.These additives are not oils, lipids, or polymers. The therapeutic agentis not enclosed in micelles or liposomes or encapsulated in polymerparticles.

Embodiments of the present invention provide a method for treating thelung during an acute episode of reversible chronic obstructive pulmonarydisease. The coronary and peripheral diseases result from smooth musclecell proliferation. Asthma includes episodes or attacks of the airwaynarrowing, contracting and thickening via smooth muscle cellproliferation. The rapamycin, paclitaxel, and their analogues can beused for treating asthma in the lung.

Embodiments of the present invention provide a method of treatingrespiratory disorders such as asthma, chronic obstructive pulmonarydisease and chronic sinusitis in a mammal comprises administrating anantiproliferative and anti-inflammatory effective amount of rapamycin,or paclitaxel or their analogues to said mammal orally, parenterally,intravascularly, intranasally, intrabronchially, transdermally,rectally, or via an impregnated vascular stent or balloon catheter.

In one embodiment, the present invention relates to a method fortreating a respiratory disorder, such as at least one of asthma, chronicobstructive pulmonary disease, and chronic sinusitis, in a mammalcomprising administering a pharmaceutical formulation comprising aneffective amount of a drug and an additive to said mammal orally,parenterally, intravascularly, intranasally, intrabronchially,transdermally, rectally, or via an impregnated vascular stent or ballooncatheter into a body passage, wherein said drug is chosen from rapamycinand analogues thereof and paclitaxel and analogues thereof. In oneaspect of this embodiment, the respiratory disorder, such as asthma andchronic obstructive pulmonary disease, is chosen from chronicbronchitis, cystic fibrosis, interstitial fibrosis, nasal and sinusdysplasia, bronchopulmonary dysplasia and neoplasia, and emphysema. Inanother aspect of this embodiment, the administering comprises deliveryvia a mist route chosen from aerosol inhalation, dry powder inhalation,liquid inhalation, and liquid instillation. In one embodiment, the mistis produced by either a nebulizer, a hand-held meter dose inhaler (MDI),or dry powder (DPI) inhaler.

In one embodiment of the method, the additive enhances absorption of thedrug into tissue of the body passage of the respiratory and sinussystem. In another embodiment of the method, the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has an affinityto the therapeutic agent by hydrogen bonding, and a part that has anaffinity to the therapeutic agent by van der Waals interactions. Inanother embodiment, the drug is not enclosed in micelles or encapsulatedin polymer particles. In yet another embodiment, the pharmaceuticalformulation does not include oil, a lipid, or a polymer.

In one embodiment of the method, the additive is at least one of asurfactant and a chemical compound. In one embodiment, the chemicalcompound is chosen from amino alcohols, hydroxyl carboxylic acid, ester,anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugarphosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids,peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In oneembodiment, the surfactant is chosen from ionic, nonionic, aliphatic,and aromatic surfactants, PEG fatty esters, PEG omega-3 fatty esters,ether, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEGglyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters,PEG sugar esters, and derivatives thereof. In another embodiment, thechemical compound has one or more hydroxyl, amino, carbonyl, carboxyl,acid, amide or ester groups. In another embodiment, the chemicalcompound having one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide or ester groups is chosen from amino alcohols, hydroxyl carboxylicacid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules.

In another embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In one embodiment, the surfactant is chosen from PEG-fatty acids andPEG-fatty acid mono and diesters, polyethylene glycol glycerol fattyacid esters, alcohol-oil transesterification products, polyglycerylfatty acids, propylene glycol fatty acid esters, sterols and derivativesthereof, polyethylene glycol sorbitan fatty acid esters, polyethyleneglycol alkyl ethers, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, and sorbitan fattyacid esters. In another embodiment, the surfactant is chosen from estersof lauric acid, oleic acid, and stearic acid, PEG-8 laurate, PEG-8oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate,PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32dilaurate, PEG-32 dioleate, PEG-25 trioleate, PEG-60 corn glycerides,PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8 caprylic/capricglycerides, and PEG-6 caprylic/capric glycerides, PEG-6 corn oil, PEG-6almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil,PEG-6 hydrogenated palm kernel oil, PEG-6 palm kernel oil, PEG-6triolein, PEG-8 corn oil, PEG-20 corn glycerides, PEG-20 almondglycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, polyglyceryl polyricinoleate,propylene glycol monolaurate, propylene glycol ricinoleate, propyleneglycol monooleate, propylene glycol dicaprylate/dicaprate, propyleneglycol dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitan monooleate,PEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol,octoxynol, nonoxynol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucop-yranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, andderivatives thereof.

In one embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromcystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine (Aminoacids);acetic anhydride, benzoic anhydride, ascorbic acid,2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid (organic acids and anhydrides);cetotiamine; cycothiamine, dexpanthenol, niacinamide, nicotinic acid,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases, L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, gluconolactone, D-glucoheptono-1,4-lactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, erythronicacid lactone, ribonic acid lactone, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben,acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid,catechin, catechin gallate, tiletamine, ketamine, propofol, lacticacids, acetic acid, salts of any organic acid and organic amine,lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine,lactobionic acid/tromethanemine, lactobionic acid/diethanolamine, lacticacid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine,gentisic acid/meglumine, gentisic acid/tromethanemine, gensiticacid/diethanolamine, vanillic acid/meglumine, vanillicacid/tromethanemine, vanillic acid/diethanolamine, benzoicacid/meglumine, benzoic acid/tromethanemine, benzoicacid/diethanolamine, acetic acid/meglumine, acetic acid/tromethanemine,acetic acid/diethanolamine, polyglycidol, glycerols, multiglycerols, andderivatives thereof.

In one embodiment of the method, the pharmaceutical formulation furthercomprises an additional drug. In one aspect of this embodiment, theadditional drug is chosen from corticosteroids, anticholinergics,beta-agonists, non-steroidal anti-inflammatory drugs, macrolideantibiotics, bronchodilators, leukotriene receptor inhibitors, cromolynsulfate, and combinations thereof.

In one embodiment, the additive is chosen from PEG fatty esters andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, vitamins and derivatives, aminoacids, multiaminoacids andderivatives, peptides, polypeptides, proteins, quaternary ammoniumsalts, organic acids, salts and anhydrides. In another embodiment, theadditive in the coating layer overlying the surface of the balloon ischosen from p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, polyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate,polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; benzalkoniumchloride, benzethonium chloride, docecyl trimethyl ammonium bromide,sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid (ionic surfactants),cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine (amino acids);acetic anhydride, benzoic anhydride, ascorbic acid,2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid (organic acids and anhydrides);cetotiamine; cycothiamine, dexpanthenol, niacinamide, nicotinic acid,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases, L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, triethanolamine, diethanolamine,meglumine, tromethamine, glucamine, glucosamine, glucoheptonic acid,glucomic acid, gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoiclactone, gulonic acid lactone, mannoic lactone, erythronic acid lactone,ribonic acid lactone, glucosamine, glutamic acid, benzyl alcohol,benzoic acid, hydroxybenzoic acid, vanillin, vanillic acid, vanillicacid diethylamide, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, acetaminophen, ibuprofen, catechin, catechin gallate, methylparaben, ethyl paraben, propyl paraben, butyl paraben, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine above described, polyglycidol, glycerols and multiglycerols(chemical compounds with multiple hydroxyl, amino, carbonyl, carboxyl,or ester moieties).

In another aspect of this embodiment, the ionic surfactant is chosenfrom benzalkonium chloride, benzethonium chloride, cetylpyridiniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, edrophonium chloride, domiphenbromide, and dialkylesters of sodium sulfonsuccinic acid, sodium dioctylsulfosuccinate, sodium cholate, and sodium taurocholate.

In one embodiment of the method, the additive is chosen from PEG-fattyacids and PEG-fatty acid mono and diesters, polyethylene glycol glycerolfatty acid esters, alcohol-oil transesterification products,polyglyceryl fatty acids, propylene glycol fatty acid esters, sterolsand derivatives thereof, polyethylene glycol sorbitan fatty acid esters,polyethylene glycol alkyl ethers, sugars and derivatives thereof,polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropyleneblock copolymers, sorbitan fatty acid esters, fat-soluble vitamins andsalts thereof, water-soluble vitamins and amphiphilic derivativesthereof, amino acid and salts thereof, oligopeptides, peptides andproteins, and organic acids and esters and anhydrides thereof.

In another embodiment of the method, the additive is chosen from estersof lauric acid, oleic acid, and stearic acid, PEG-8 laurate, PEG-8oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate,PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20oleate. In another embodiment, the additive is chosen from PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate andPEG-32 dioleate. In another embodiment of the method, the additive ischosen from PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. Inanother embodiment of the method, the additive is chosen from PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, and PEG-6 caprylic/capricglycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil,PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil,PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 cornglycerides, and PEG-20 almond glycerides.

In another embodiment of the method, the additive is chosen frompolyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,polyglyceryl stearate, polyglyceryl laurate, polyglyceryl myristate,polyglyceryl palmitate, and polyglyceryl linoleate, polyglyceryl-10laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate, andpolyglyceryl polyricinoleate. In another embodiment of the method, theadditive is chosen from propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, and propylene glycol dioctanoate. In anotherembodiment of the method, the additive is PEG-24 cholesterol ether. Inanother embodiment of the method, the additive is chosen from sterolpolyethylene glycol derivatives.

In another embodiment of the method, the additive is chosen from PEG-20sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, and PEG-20 sorbitan monooleate. In another embodiment ofthe method, the additive is chosen from PEG-3 oleyl ether and PEG-4lauryl ether. In another embodiment of the method, the additive ischosen from sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucop-yranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, and octyl-β-D-thioglucopyranoside.

In another embodiment of the method, the additive is chosen fromPEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol,octoxynol, and nonoxynol. In another embodiment of the method, theadditive is chosen from poloxamer 108, poloxamer 188, poloxamer 217,poloxamer 238, poloxamer 288, poloxamer 338, and poloxamer 407. Inanother embodiment of the method, the additive is chosen from poloxamer124, poloxamer 182, poloxamer 183, poloxamer 212, poloxamer 331, andpoloxamer 335. In another embodiment of the method, the additive ischosen from sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, and sorbitan monostearate. In another embodiment of themethod, the additive is chosen from alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II), and folic acid.

In another embodiment of the method, the additive is chosen fromacetiamine, benfotiamine, pantothenic acid, cetotiamine, cycothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU. In another embodiment of the method, the additive is chosen fromalanine, arginine, asparagines, aspartic acid, cysteine, glutamic acid,glutamine, glycine, histidine, proline, isoleucine, leucine, lysine,methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, andvaline, and salts of any of the foregoing. In another embodiment of themethod, the additive is albumin. In another embodiment of the method,the additive is chosen from n-octyl-β-D-glucopyranoside, octoxynol-9,Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, L-ascorbic acid,thiamine, maleic anhydride, niacinamide, and 2-pyrrolidone-5-carboxylicacid.

In another embodiment of the method, the additive is chosen fromriboflavin, riboflavin-phosphate sodium, Vitamin D3, folic acid, vitamin12, diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine.

In another embodiment of the method, the additive is chosen fromisononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate. In anotherembodiment of the method, the additive is chosen from L-ascorbic acid,thiamine, maleic acids, niacinamide, and 2-pyrrolidone-5-carboxylicacid. In another embodiment of the method, the additive is chosen fromVitamin D2 and D3.

In one embodiment, the present invention relates to a pharmaceuticalformulation comprising an effective amount of a drug for treatment of arespiratory or sinus system, and an additive that enhances absorption ofthe drug into tissue of the respiratory system. In one aspect of thisembodiment, the additive comprises a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions. In another aspect of thisembodiment, the drug is not enclosed in micelles or encapsulated inpolymer particles. In another aspect of this embodiment, the formulationdoes not include oil, a lipid, or a polymer. In yet another aspect ofthis embodiment, the formulation is an aqueous aerosol formulation, adry powder aerosol formulation, or a propellant-based formulation.

In one embodiment of the pharmaceutical formulation, the drug is chosenfrom paclitaxel and analogues thereof and rapamycin and analoguesthereof. In one aspect of this embodiment, the drug is present in aconcentration of about 0.05 mg/ml to about 600 mg/ml.

In one embodiment of the pharmaceutical formulation, the additive is atleast one of a surfactant and a chemical compound. In one embodiment,the chemical compound is chosen from amino alcohols, hydroxyl carboxylicacid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In oneembodiment, the surfactant is chosen from ionic, nonionic, aliphatic,and aromatic surfactants, PEG fatty esters, PEG omega-3 fatty esters,ether, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEGglyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters,PEG sugar esters, and derivatives thereof. In one embodiment, thechemical compound has one or more hydroxyl, amino, carbonyl, carboxyl,acid, amide or ester groups. In one aspect of this embodiment, thechemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from amino alcohols,hydroxyl carboxylic acid, ester, anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohol and organic acid, and theirsubstituted molecules. In another aspect of this embodiment, thechemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from cystine, tyrosine,tryptophan, leucine, isoleucine, phenylalanine, asparagine, asparticacid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid,gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,gulonic acid lactone, mannoic lactone, erythronic acid lactone, ribonicacid lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine above described, lysine/glutamicacid, lysine acetate, lactobionic acid/meglumine, lactobionicacid/tromethanemine, lactobionic acid/diethanolamine, lacticacid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine,gentisic acid/meglumine, gentisic acid/tromethanemine, gensiticacid/diethanolamine, vanillic acid/meglumine, vanillicacid/tromethanemine, vanillic acid/diethanolamine, benzoicacid/meglumine, benzoic acid/tromethanemine, benzoicacid/diethanolamine, acetic acid/meglumine, acetic acid/tromethanemine,and acetic acid/diethanolamine, polyglycidol, glycerols, multiglycerolsand a mixture of the additives, and their derivatives.

In one embodiment of the pharmaceutical formulation, the additive ischosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In one embodiment of the pharmaceutical formulation, the surfactant ischosen from esters of lauric acid, oleic acid, and stearic acid, PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl laurate,PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryloleate, PEG-30 glyceryl oleate, PEG-25 trioleate, PEG-60 cornglycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, PEG-6 cornoil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6 palm kernel oil,PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides, PEG-20 almondglycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, and polyglycerylpolyricinoleate, propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl ether and PEG-4lauryl ether, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucop-yranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, PEG-10-100nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), n-octyl-β-D-glucopyranoside,octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, and theirderivatives.

In one embodiment of the pharmaceutical formulation, the additive ischosen from from PEG-fatty acids and PEG-fatty acid mono and diesters,polyethylene glycol glycerol fatty acid esters, alcohol-oiltransesterification products, polyglyceryl fatty acids, propylene glycolfatty acid esters, sterol and derivatives thereof, polyethylene glycolsorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugars andderivatives thereof, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters, fat-soluble vitamins and salts thereof, water-soluble vitaminsand amphiphilic derivatives thereof, amino acid and salts thereof,oligopeptides, peptides and proteins, and organic acids and esters andanhydrides thereof. In another embodiment of the pharmaceuticalformulation, the additive is chosen from esters of lauric acid, oleicacid, and stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate,PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20 oleate.

In one embodiment of the pharmaceutical formulation, the additive ischosen from PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32dilaurate and PEG-32 dioleate. In another embodiment of thepharmaceutical formulation, the additive is chosen from PEG-20 glyceryllaurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20glyceryl oleate, and PEG-30 glyceryl oleate. In another embodiment ofthe pharmaceutical formulation, the additive is chosen from PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides,PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 oliveoil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6 palmkernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides, andPEG-20 almond glycerides.

In one embodiment of the pharmaceutical formulation, the additive ischosen from polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, and polyglycerylpolyricinoleate. In another embodiment of the pharmaceuticalformulation, the additive is chosen from propylene glycol monolaurate,propylene glycol ricinoleate, propylene glycol monooleate, propyleneglycol dicaprylate/dicaprate, and propylene glycol dioctanoate.

In one embodiment of the pharmaceutical formulation, the additive isPEG-24 cholesterol ether. In another embodiment of the pharmaceuticalformulation, the additive is chosen from sterol polyethylene glycolderivatives. In another embodiment of the pharmaceutical formulation,the additive is chosen from PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 sorbitan monostearate, and PEG-20 sorbitanmonooleate. In another embodiment of the pharmaceutical formulation, theadditive is chosen from PEG-3 oleyl ether and PEG-4 lauryl ether.

In one embodiment of the pharmaceutical formulation, the additive ischosen from sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucop-yranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, and octyl-β-D-thioglucopyranoside. Inanother embodiment of the pharmaceutical formulation, the additive ischosen from PEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether,Tyloxapol, octoxynol, and nonoxynol. In another embodiment of thepharmaceutical formulation, the additive is chosen from poloxamer 108,poloxamer 188, poloxamer 217, poloxamer 238, poloxamer 288, poloxamer338, and poloxamer 407. In another embodiment of the pharmaceuticalformulation, the additive is chosen from poloxamer 124, poloxamer 182,poloxamer 183, poloxamer 212, poloxamer 331, and poloxamer 335.

In one embodiment of the pharmaceutical formulation, the additive ischosen from sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, and sorbitan monostearate. In another embodiment of thepharmaceutical formulation, the additive is chosen fromalpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol,tocopherol acetate, ergosterol, 1-alpha-hydroxycholecal-ciferol, vitaminD2, vitamin D3, alpha-carotene, beta-carotene, gamma-carotene, vitaminA, fursultiamine, methylolriboflavin, octotiamine, prosultiamine,riboflavine, vintiamol, dihydrovitamin K1, menadiol diacetate, menadioldibutyrate, menadiol disulfate, menadiol, vitamin K1, vitamin K1 oxide,vitamins K2, and vitamin K-S(II), and folic acid.

In another embodiment of the pharmaceutical formulation, the additive ischosen from acetiamine, benfotiamine, pantothenic acid, cetotiamine,cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU. In another embodiment of the pharmaceutical formulation, the additiveis chosen from alanine, arginine, asparagines, aspartic acid, cysteine,cystine, glutamic acid, glutamine, glycine, histidine, proline,isoleucine, leucine, lysine, methionine, phenylalanine, serine,threonine, tryptophan, tyrosine, and valine, and salts of any of theforegoing. In another embodiment of the pharmaceutical formulation, theadditive is albumin.

In one embodiment of the pharmaceutical formulation, the additive ischosen from n-octyl-β-D-glucopyranoside, octoxynol-9, Polysorbates,Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEGglyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10stearate, L-ascorbic acid, thiamine, maleic anhydride, niacinamide, and2-pyrrolidone-5-carboxylic acid. In another embodiment of thepharmaceutical formulation, the additive is chosen from riboflavin,riboflavin-phosphate sodium, Vitamin D3, folic acid, vitamin 12,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine.

In one embodiment of the pharmaceutical formulation, the additive ischosen from isononylphenylpolyglycidol, PEG glyceryl monooleate,sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,sorbitan monostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate. In anotherembodiment of the pharmaceutical formulation, the additive is chosenfrom L-ascorbic acid, thiamine, maleic acids, niacinamide, and2-pyrrolidone-5-carboxylic acid. In another embodiment of thepharmaceutical formulation, the additive is chosen from Vitamin D2 andD3.

In one embodiment of the pharmaceutical formulation, the drug is presentin a concentration of about 0.05 mg/g to about 990 mg/g. In anotherembodiment of the pharmaceutical formulation, the formulation furthercomprises an additional drug. In one aspect of this embodiment, theadditional drug is chosen from corticosteroids, anticholinergics,beta-agonists, non-steroidal anti-inflammatory drugs, macrolideantibiotics, bronchodilators, leukotriene receptor inhibitors, cromolynsulfate, and combinations thereof.

In one embodiment, the present invention relates to a method fortreating a respiratory system in a mammal comprising (1) forming anaerosol of a dispersion of particles, wherein the particles comprise awater insoluble drug and an additive that enhances absorption of thedrug into tissue of the respiratory system, and (2) administering theaerosol to the respiratory system of the mammal. In one aspect of thisembodiment, the additive comprises a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions. In another aspect of thisembodiment, the drug is not enclosed in micelles or encapsulated inpolymer particles. In another aspect of this embodiment, the dispersiondoes not include oil, a lipid, or a polymer. In another aspect of thisembodiment, the dispersion does not include a purely hydrophobicadditive.

In one embodiment, the additive is at least one of a surfactant and achemical compound. In one embodiment, the chemical compound is chosenfrom amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules. In one embodiment, thesurfactant is chosen from ionic, nonionic, aliphatic, and aromaticsurfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof. In one embodiment, the chemicalcompound has one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide or ester groups. In one aspect of this embodiment, the chemicalcompound having one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide or ester groups is chosen from amino alcohols, hydroxyl carboxylicacid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In anotheraspect of this embodiment, the chemical compound having one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups ischosen from cystine, tyrosine, tryptophan, leucine, isoleucine,phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine;acetic anhydride, benzoic anhydride, ascorbic acid,2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid; cetotiamine; cycothiamine, dexpanthenol,niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamideascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid,menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitaminB12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases,benzalkonium chloride, L-ascorbic acid and its salt, D-glucoascorbicacid and its salt, tromethamine, triethanolamine, diethanolamine,meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid,gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,gulonic acid lactone, mannoic lactone, erythronic acid lactone, ribonicacid lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine above described, lysine/glutamicacid, lysine acetate, lactobionic acid/meglumine, lactobionicacid/tromethanemine, lactobionic acid/diethanolamine, lacticacid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine,gentisic acid/meglumine, gentisic acid/tromethanemine, gensiticacid/diethanolamine, vanillic acid/meglumine, vanillicacid/tromethanemine, vanillic acid/diethanolamine, benzoicacid/meglumine, benzoic acid/tromethanemine, benzoicacid/diethanolamine, acetic acid/meglumine, acetic acid/tromethanemine,acetic acid/diethanolamine, polyglycidol, glycerols, multiglycerols anda mixture of the additives, and their derivatives.

In one embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In one embodiment, the additive is chosen from PEG-fatty acids andPEG-fatty acid mono and diesters, polyethylene glycol glycerol fattyacid esters, alcohol-oil transesterification products, polyglycerylfatty acids, propylene glycol fatty acid esters, sterol and derivativesthereof, polyethylene glycol sorbitan fatty acid esters, polyethyleneglycol alkyl ethers, sugars and derivatives thereof, polyethylene glycolalkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,water-soluble vitamins and amphiphilic derivatives thereof, amino acidand salts thereof, oligopeptides, peptides and proteins, and organicacids and esters and anhydrides thereof. In yet another aspect of thisembodiment, the water insoluble drug is chosen from paclitaxel andanalogues thereof and rapamycin and analogues thereof.

In one embodiment, the surfactant is chosen from esters of lauric acid,oleic acid, and stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate,PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides,PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 oliveoil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6 palmkernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides,PEG-20 almond glycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, and polyglycerylpolyricinoleate, propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl ether and PEG-4lauryl ether, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucop-yranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, PEG-10-100nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), n-octyl-β-D-glucopyranoside,octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, and theirderivatives.

In one embodiment, the water insoluble drug is chosen from paclitaxeland analogues thereof and rapamycin and analogues thereof.

In one embodiment, the present invention relates to an aerosol devicefor delivering a drug to a respiratory system, the device comprising apharmaceutical formulation comprising a water insoluble drug and anadditive, wherein the additive enhances absorption of the drug intotissue of the respiratory system. In one aspect of this embodiment, thepharmaceutical formulation is an aqueous, propellant based, or drypowder formulation. In another aspect of this embodiment, the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions.In another aspect of this embodiment, the drug is not enclosed inmicelles or encapsulated in polymer particles. In another aspect of thisembodiment, the formulation does not include oil, a lipid, or a polymer.In another aspect of this embodiment, the additive is chosen fromPEG-fatty acids and PEG-fatty acid mono and diesters, polyethyleneglycol glycerol fatty acid esters, alcohol-oil transesterificationproducts, polyglyceryl fatty acids, propylene glycol fatty acid esters,sterol and derivatives thereof, polyethylene glycol sorbitan fatty acidesters, polyethylene glycol alkyl ethers, sugars and derivativesthereof, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters, fat-soluble vitamins and salts thereof, water-soluble vitaminsand amphiphilic derivatives thereof, amino acid and salts thereof,oligopeptides, peptides and proteins, and organic acids and esters andanhydrides thereof. In another aspect of this embodiment, the waterinsoluble drug is chosen from paclitaxel and analogues thereof andrapamycin and analogues thereof. In yet another aspect of thisembodiment, the aerosol device is one of a nebulizer, a hand-held meterdose inhaler, or a dry powder inhaler.

In another embodiment, the additive is at least one of a surfactant anda chemical compound. In one embodiment, the chemical compound is chosenfrom amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules. In one embodiment, thesurfactant is chosen from ionic, nonionic, aliphatic, and aromaticsurfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof.

In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect ofthis embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromamino alcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules. In another aspect of this embodiment,the chemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from cystine, tyrosine,tryptophan, leucine, isoleucine, phenylalanine, asparagine, asparticacid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid,gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,gulonic acid lactone, mannoic lactone, erythronic acid lactone, ribonicacid lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine above described, lysine/glutamicacid, lysine acetate, lactobionic acid/meglumine, lactobionicacid/tromethanemine, lactobionic acid/diethanolamine, lacticacid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine,gentisic acid/meglumine, gentisic acid/tromethanemine, gensiticacid/diethanolamine, vanillic acid/meglumine, vanillicacid/tromethanemine, vanillic acid/diethanolamine, benzoicacid/meglumine, benzoic acid/tromethanemine, benzoicacid/diethanolamine, acetic acid/meglumine, acetic acid/tromethanemine,acetic acid/diethanolamine, polyglycidol, glycerols, multiglycerols anda mixture of the additives, and their derivatives.

In one embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In one embodiment, the surfactant is chosen from esters of lauric acid,oleic acid, and stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate,PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides,PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 oliveoil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6 palmkernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides,PEG-20 almond glycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, and polyglycerylpolyricinoleate, propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl ether and PEG-4lauryl ether, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, PEG-10-100nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), n-octyl-β-D-glucopyranoside,octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, and theirderivatives.

In one embodiment, the water insoluble drug is chosen from paclitaxeland analogues thereof and rapamycin and analogues thereof. In oneembodiment, the aerosol device is one of a nebulizer, a hand-held meterdose inhaler, or a dry powder inhaler.

In one embodiment, the present invention relates to a device sized andconfigured for insertion into a passage of a respiratory system, thedevice comprising a layer overlying an exterior surface of the device,the layer comprising a water insoluble drug for the treatment of therespiratory system and an additive that enhances absorption of the druginto tissue of the respiratory system. In one aspect of this embodiment,the additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions. In another aspect of this embodiment, the drug isnot enclosed in micelles or encapsulated in polymer particles. Inanother aspect of this embodiment, the layer does not include oil, alipid, or a polymer. In another aspect of this embodiment, the layerdoes not include a purely hydrophobic additive. In another aspect ofthis embodiment, the device is a balloon catheter or a stent. In anotheraspect of this embodiment, the water insoluble drug is chosen frompaclitaxel and analogues thereof and rapamycin and analogues thereof. Inanother aspect of this embodiment, the additive is chosen from PEG-fattyacids and PEG-fatty acid mono and diesters, polyethylene glycol glycerolfatty acid esters, alcohol-oil transesterification products,polyglyceryl fatty acids, propylene glycol fatty acid esters, sterol andderivatives thereof, polyethylene glycol sorbitan fatty acid esters,polyethylene glycol alkyl ethers, sugars and derivatives thereof,polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropyleneblock copolymers, sorbitan fatty acid esters, fat-soluble vitamins andsalts thereof, water-soluble vitamins and amphiphilic derivativesthereof, amino acid and salts thereof, oligopeptides, peptides andproteins, and organic acids and esters and anhydrides thereof.

In one embodiment, the additive is at least one of a surfactant and achemical compound. In one embodiment, the chemical compound is chosenfrom amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules. In one embodiment, thesurfactant is chosen from ionic, nonionic, aliphatic, and aromaticsurfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof.

In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect ofthis embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromamino alcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules. In another aspect of this embodiment,the chemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from cystine, tyrosine,tryptophan, leucine, isoleucine, phenylalanine, asparagine, asparticacid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, maleic and anhydride, succinic anhydride,diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine,pantothenic acid; cetotiamine; cycothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases,L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,tromethamine, triethanolamine, diethanolamine, meglumine, glucamine,amine alcohols, glucoheptonic acid, glucomic acid, gluconolactone,D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, erythronic acid lactone, ribonic acid lactone,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin,methyl paraben, propyl paraben, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine above described, lysine/glutamic acid, lysine acetate,lactobionic acid/meglumine, lactobionic acid/tromethanemine, lactobionicacid/diethanolamine, lactic acid/meglumine, lactic acid/tromethanemine,lactic acid/diethanolamine, gentisic acid/meglumine, gentisicacid/tromethanemine, gensitic acid/diethanolamine, vanillicacid/meglumine, vanillic acid/tromethanemine, vanillicacid/diethanolamine, benzoic acid/meglumine, benzoicacid/tromethanemine, benzoic acid/diethanolamine, acetic acid/meglumine,acetic acid/tromethanemine, acetic acid/diethanolamine, polyglycidol,glycerols, multiglycerols and a mixture of the additives, and theirderivatives.

In one embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In one embodiment, the surfactant is chosen from esters of lauric acid,oleic acid, and stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate,PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides,PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 oliveoil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6 palmkernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides,PEG-20 almond glycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, and polyglycerylpolyricinoleate, propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl ether and PEG-4lauryl ether, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucop-yranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, PEG-10-100nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), n-octyl-β-D-glucopyranoside,octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, and theirderivatives.

In one embodiment, the present invention relates to a method fortreating a respiratory system comprising inserting a balloon cathetercomprising a coating layer into an airway, wherein the coating layercomprises a drug and an additive, inflating the balloon catheter andreleasing the drug to a wall of the airway, deflating the balloon; andwithdrawing the balloon catheter from the airway. In one aspect of thisembodiment, the additive enhances absorption of the drug into tissue ofthe respiratory or sinus system. In another aspect of this embodiment,the additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions. In another aspect of this embodiment, the drug isnot enclosed in micelles or encapsulated in polymer particles. Inanother aspect of this embodiment, the coating layer does not includeoil, a lipid, or a polymer. In another aspect of this embodiment, thecoating layer does not include a purely hydrophobic additive. In anotheraspect of this embodiment, the drug is chosen from paclitaxel andanalogues thereof and rapamycin and analogues thereof. In another aspectof this embodiment, the additive is chosen from PEG-fatty acids andPEG-fatty acid mono and diesters, polyethylene glycol glycerol fattyacid esters, alcohol-oil transesterification products, polyglycerylfatty acids, propylene glycol fatty acid esters, sterol and derivativesthereof, polyethylene glycol sorbitan fatty acid esters, polyethyleneglycol alkyl ethers, sugars and derivatives thereof, polyethylene glycolalkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,water-soluble vitamins and amphiphilic derivatives thereof, amino acidand salts thereof, oligopeptides, peptides and proteins, and organicacids and esters and anhydrides thereof. In yet another aspect of thisembodiment, the drug can be released to the wall of the airway prior to,during, or after an asthma attack.

In one embodiment, the additive is at least one of a surfactant and achemical compound. In one embodiment, the chemical compound is chosenfrom amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules. In one embodiment, thesurfactant is chosen from ionic, nonionic, aliphatic, and aromaticsurfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof.

In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect ofthis embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromamino alcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules.

In one embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Embodiments of the present invention provide a method for treatment ofrespiratory disorders such as asthma, chronic obstructive pulmonarydisease and chronic sinusitis, including cystic fibrosis, interstitialfibrosis, chronic bronchitis, emphysema, nasal and sinus dysplasia,bronchopulmonary dysplasia and neoplasia. According to embodiments, themethod involves administration, preferably oral or pulmonaryadministration, of anti-inflammatory and anti-proliferate drugs(rapamycin or paclitaxel and their analogues). The anti-inflammatory andanti-proliferate drugs can be administered alone or with one or moreadditives.

The anti-inflammatory and anti-proliferate drugs intended for intranasaldelivery (systemic and local) for treatment of respiratory disorderssuch as asthma, COPD and chronic sinusitis can be, administered asaqueous solutions or suspensions, as solutions or suspensions inhalogenated hydrocarbon propellants (pressurized metered-dose inhalers),or as dry powders. Metered-dose spray pumps for aqueous formulations,pMDIs, and DPIs for nasal delivery, are available from, for example,Valois of America or Pfeiffer of America.

The drugs intended for pulmonary delivery can also be administered asaqueous formulations, as suspensions or solutions in halogenatedhydrocarbon propellants, or as dry powders. Aqueous formulations must beaerosolized by liquid nebulizers employing either hydraulic orultrasonic atomization, propellant-based systems require suitablepressurized metered-dose inhalers (pMDIs), and dry powders require drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. For aqueous and other non-pressurized liquidsystems, a variety of nebulizers (including small volume nebulizers) areavailable to aerosolize the formulations. Compressor-driven nebulizersincorporate jet technology and use compressed air to generate the liquidaerosol. Such devices are commercially available from, for example,Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain MedicalEquipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.;Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak,Inc. Ultrasonic nebulizers rely on mechanical energy in the form ofvibration of a piezoelectric crystal to generate respirable liquiddroplets and are commercially available from, for example, OmronHealthcare, Inc. and DeVilbiss Health Care, Inc.

A propellant driven inhaler (pMDI) releases a metered dose of medicineupon each actuation. The medicine is formulated as a suspension orsolution of a drug substance in a suitable propellant such as ahalogenated hydrocarbon. pMDIs are described in, for example, Newman, S.P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224(Butterworths, London, England, 1984).

Dry powder inhalers (DPIs), which involve disaggregation andaerosolization of dry powders, normally rely upon a burst of inspiredair that is drawn through the unit to deliver a drug dosage. Suchdevices are described in, for example, U.S. Pat. No. 4,807,814, which isdirected to a pneumatic powder ejector having a suction stage and aninjection stage; SU 628930 (Abstract), describing a hand-held powderdisperser having an axial air flow tube; Fox et al., Powder and BulkEngineering, pages 33-36 (March 1988), describing a venturi eductorhaving an axial air inlet tube upstream of a venturi restriction; EP 347779, describing a hand-held powder disperser having a collapsibleexpansion chamber; and U.S. Pat. No. 5,785,049 directed to dry powderdelivery devices for drugs.

Droplet/particle size determines deposition site. In developing thetherapeutic aerosol of the anti-inflammatory and anti-proliferate drugs,the aerodynamic size distribution of the inhaled particles is the singlemost important variable in defining the site of droplet or particledeposition in the patient; in short, it will determine whether drugtargeting succeeds or fails. See P. Byron, “Aerosol Formulation,Generation, and Delivery Using Nonmetered Systems,” Respiratory DrugDelivery, 144-151, 144 (CRC Press, 1989). Thus, a prerequisite indeveloping a therapeutic aerosol is a preferential particle size. Thedeposition of inhaled aerosols involves different mechanisms fordifferent size particles. D. Swift (1980); Parodi et al., “AirborneParticles and Their Pulmonary Deposition,” in Scientific Foundations ofRespiratory Medicine, Scaddings et al. (eds.), pp. 545-557 (W. B.Saunders, Philadelphia, 1981); J. Heyder, “Mechanism of Aerosol ParticleDeposition,” Chest, 80:820-823 (1981).

Generally, inhaled particles are subject to deposition by one of twomechanisms: impaction, which usually predominates for larger particles,and sedimentation, which is prevalent for smaller particles. Impactionoccurs when the momentum of an inhaled particle is large enough that theparticle does not follow the air stream and encounters a physiologicalsurface. In contrast, sedimentation occurs primarily in the deep lungwhen very small particles which have traveled with the inhaled airstream encounter physiological surfaces as a result of random diffusionwithin the air stream. For intranasally administered drug compoundswhich are inhaled through the nose, it is desirable for the drug toimpact directly on the nasal mucosa; thus, large (ca. 5 to 100 microns)particles or droplets are generally preferred for targeting of nasaldelivery.

Pulmonary drug delivery of the anti-inflammatory and anti-proliferativedrugs is accomplished by inhalation of an aerosol through the mouth andthroat. Particles having aerodynamic diameters of greater than about 5microns generally do not reach the lung; instead, they tend to impactthe back of the throat and are swallowed and possibly orally absorbed.Particles having diameters of about 2 to about 5 microns are smallenough to reach the upper- to mid-pulmonary region (conducting airways),but are too large to reach the alveoli. Even smaller particles, i. e.,about 0.5 to about 2 microns, are capable of reaching the alveolarregion. Particles having diameters smaller than about 0.5 microns canalso be deposited in the alveolar region by sedimentation, although verysmall particles may be exhaled.

Embodiments of the present invention are directed to aqueous,propellant-based, and dry powder aerosols of anti-inflammatory andanti-proliferate drug compositions, for pulmonary delivery, in whichessentially every inhaled particle contains at least oneanti-inflammatory and anti-proliferate drug particle. The drug is highlywater-insoluble. Preferably, the anti-inflammatory and anti-proliferatedrug has an effective average particle size of about 5 micron or less.

A. Aqueous Aerosol Formulations

Embodiments of the present invention encompass aqueous formulationscomprising drug particles and an additive. For aqueous aerosolformulations, the anti-inflammatory and anti-proliferate drug may bepresent at a concentration of about 0.05 mg/ml up to about 600 mg/ML.Such formulations provide effective delivery to appropriate areas of thelung. In addition, the more concentrated aerosol formulations (i.e., foraqueous aerosol formulations, about 10 mg/ml up to about 600 mg/ml) havethe additional advantage of enabling large quantities of drug substanceto be delivered to the lung in a very short period of time.

B. Dry Powder Aerosol Formulations

Another embodiment of the invention is directed to dry powder aerosolformulations comprising anti-inflammatory and anti-proliferate drugparticles and an additive for pulmonary and nasal administration. Drypowders, which can be used in both DPIs and pMDIs, can be made by spraydrying aqueous drug dispersions. Alternatively, dry powders containinganti-inflammatory and anti-proliferate drug can be made by freeze-dryingdrug dispersions. Combinations of spray-dried and freeze-dried drugpowders can be used in DPIs and pMDIs. For dry powder aerosolformulations, the anti-inflammatory and anti-proliferate drug may bepresent at a concentration of about 0.05 mg/g up to about 990 mg/g.

1. Spray-Dried Powders Containing Anti-Inflammatory and Anti-ProliferateDrug

Powders comprising anti-inflammatory and anti-proliferate drug can bemade by spray-drying aqueous dispersions of a drug and an additive toform a dry powder which consists of aggregated drug particles having anadditive. The aggregates can have a size of about 1 to about 2 microns,which is suitable for deep lung delivery. The aggregate particle sizecan be increased to target alternative delivery sites, such as the upperbronchial region or nasal mucosa by increasing the concentration of drugin the spray-dried dispersion or by increasing the droplet sizegenerated by the spray dryer.

Alternatively, the aqueous dispersion of the anti-inflammatory andanti-proliferate drug and additive can contain a dissolved diluent suchas lactose or mannitol which, when spray dried, forms respirable diluentparticles, each of which contains at least one embedded drug particleand additive. The diluent particles with embedded drug can have aparticle size of about 1 to about 2 microns, suitable for deep lungdelivery. In addition, the diluent particle size can be increased totarget alternate delivery sites, such as the upper bronchial region ornasal mucosa by increasing the concentration of dissolved diluent in theaqueous dispersion prior to spray drying, or by increasing the dropletsize generated by the spray dryer.

Spray-dried powders can be used in DPIs or pMDIs, either alone orcombined with freeze-dried particulate powder. In addition, spray-driedpowders containing drug particles can be reconstituted and used ineither jet or ultrasonic nebulizers to generate aqueous dispersionshaving respirable droplet sizes, where each droplet contains at leastone drug particle. Concentrated particulate dispersions may also be usedin these aspects of the invention.

2. Freeze-Dried Powders Containing Anti-Inflammatory andAnti-Proliferative Particulate Drug

The particulate drug dispersions can also be freeze-dried to obtainpowders suitable for nasal or pulmonary delivery. Such powders maycontain aggregated particulate drug particles having an additive. Suchaggregates may have sizes within a respirable range, i.e., about 2 toabout 5 microns.

Freeze dried powders of the appropriate particle size can also beobtained by freeze drying aqueous dispersions of the anti-inflammatoryand anti-proliferative drug and additive, which additionally contain adissolved diluent such as lactose or mannitol. In these instances thefreeze dried powders consist of respirable particles of diluent, each ofwhich contains at least one embedded drug particle.

Freeze-dried powders can be used in DPIs or pMDIs, either alone orcombined with spray-dried particulate powder. In addition, freeze-driedpowders containing drug particles can be reconstituted and used ineither jet or ultrasonic nebulizers to generate aqueous dispersionshaving respirable droplet sizes, where each droplet contains at leastone drug particle. Concentrated particulate dispersions may also be usedin these aspects of the invention.

C. Propellant-Based Formulations

Yet another embodiment of the invention is directed to a process andcomposition for propellant-based systems comprising anti-inflammatoryand anti-proliferative drug particles and an additive. Such formulationsmay be prepared by wet milling the coarse drug substance and additive inliquid propellant, either at ambient pressure or under high pressureconditions. Alternatively, dry powders containing drug particles may beprepared by spray-drying or freeze-drying aqueous dispersions of drugparticles and additive; the resultant powders are dispersed intosuitable propellants for use in conventional pMDIs. Such particulatepMDI formulations can be used for either nasal or pulmonary delivery.For pulmonary administration, such formulations afford increaseddelivery to the deep lung regions because of the small (i.e., about 1 toabout 2 microns) particle sizes available from these methods.Concentrated aerosol formulations can also be employed in pMDIs.

D. Methods of Making Aerosol Formulations

In embodiments, the invention also provides methods for making anaerosol comprising a drug particulate composition comprising ananti-inflammatory and anti-proliferate and an additive. The particulatedispersions used in making aqueous aerosol compositions can be made bywet milling or by precipitation methods known in the art. Dry powderscontaining the drug particles and additive can be made by spray-dryingor freeze-drying aqueous dispersions of the anti-inflammatory andanti-proliferate drug particles and the additive. The dispersions usedin these systems may or may not contain dissolved diluent material priorto drying. Additionally, both pressurized and non-pressurized millingoperations can be employed to make particulate drug compositions innon-aqueous systems.

In a non-aqueous, non-pressurized milling system, a non-aqueous liquidwhich has a vapor pressure of 1 atm or less at room temperature is usedas a milling medium and may be evaporated to yield dry particulate drugand additive. The non-aqueous liquid may be, for example, a high-boilinghalogenated hydrocarbon. The dry particulate drug composition thusproduced may then be mixed with a suitable propellant or propellants andused in a conventional pMDI.

Alternatively, in a pressurized milling operation, a non-aqueous liquidwhich has a vapor pressure >1 atm at room temperature is used as amilling medium for making a particulate drug and additive composition.Such a liquid may be, for example, a halogenated hydrocarbon propellantwhich has a low boiling point. The resultant particulate composition canthen be used in a conventional pMDI without further modification, or canbe blended with other suitable propellants. Concentrated aerosols mayalso be made via such methods.

E. Methods of Using Particulate Aerosol Formulations

In yet another aspect of the invention, there is provided a method oftreating asthma and COPD of mammals comprising: (1) forming an aerosolof a dispersion (either aqueous or powder) of the anti-inflammatory andanti-proliferate drug particles, wherein the particles comprise aninsoluble drug having an additive on the surface thereof, and (2)administering the aerosol to the pulmonary or nasal cavities of themammal. Concentrated aerosol formulations may also be used in suchmethods.

Drugs and Drug Combinations

The therapeutic drug or agent in the invention comprises one or moredrugs or agents chosen from an anti-thrombosis agent, ananti-proliferate agent, an anti-inflammatory agent, an anti-coagulant,an agent affecting extra cellular matrix production and organization,and a vasodilating agent.

Examples of the therapeutic agents or drugs that are suitable for use inaccordance with the present invention include sirolimus, everolimus,actinomycin D (ActD), taxol, paclitaxel, or derivatives and analogsthereof. Examples of agents include other antiproliferative substancesas well as antineoplastic, antiinflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, andantioxidant substances. Examples of antineoplastics include taxol(paclitaxel and docetaxel). Further examples of therapeutic drugs oragents include antiplatelets, anticoagulants, antifibrins,antiinflammatories, antithrombins, and antiproliferatives. Examples ofantiplatelets, anticoagulants, antifibrins, and antithrombins include,but are not limited to, sodium heparin, low molecular weight heparin,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogs, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist, recombinant hirudin, thrombin inhibitor (availablefrom Biogen located in Cambridge, Mass.), and 7E-3B® (An antiplateletdrug from Centocor located in Malvern, Pa.). Examples of antimitoticagents include methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, adriamycin, and mutamycin. Examples of cytostatic orantiproliferative agents include angiopeptin (a somatostatin analog fromIbsen located in the United Kingdom), angiotensin converting enzymeinhibitors such as Captopril® (available from Squibb located in NewYork, N.Y.), Cilazapril® (available from Hoffman-LaRoche located inBasel, Switzerland), or Lisinopril® (available from Merck located inWhitehouse Station, N.J.); calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, Lovastatin® (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug from Merck),methotrexate, monoclonal antibodies (such as PDGF receptors),nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitor(available from GlaxoSmithKline located in United Kingdom), Seramin (aPDGF antagonist), serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. Othertherapeutic drugs or agents which may be appropriate includealpha-interferon, genetically engineered epithelial cells, anddexamethasone.

An anti-thrombosis agent, an anti-proliferate agent, ananti-inflammatory agent, especially rapamycin or paclitaxel and theiranalogues, as discussed above, can be used in combination with otherdrugs, such as inhaled corticosteroids, inhaled anticholinergics such asipratropium and beta-agonists such as albuterol, inhaled leukotrieneinhibitors, and inhaled epinephrine.

Some drugs that are considered particularly suitable for the combinationare inhaled corticosteroids such as, Budesonide, Flunisolide,Triamcinolone, Beclomethasone, Fluticasone, Mometasone, Dexamethasone,Hydrocortisone, Methylprednisolone, Prednisone, Cortisone,Betamethasone, or the like. Some other suitable drugs arebronchodilators such as Terbutaline, Albuterol, Ipratropium, Pirbuterol,Epinephrine, Salmeterol, Levalbuterol, Formoterol, or the like.

Other drugs that are also considered to be suitably administered in thecombinations include, but are not limited to, Leukotriene inhibitorssuch as Montelukast, Zafirlukast, Zileuton, or the like; antihistaminessuch as Loratadine, Cetirizine or the like; Anti-Tuberculosis drugs forM TB or atypical mycobacteria such as, Isoniazid, Ethambutol,Pyrazinamide, Rifamycin; Rifampin, Streptomycin, Clarithromycin, or thelike; other drugs; such as the Serine lung protease inhibitorsAzelastine, and Theophylline; and other peptides, such as those thatrelate to Allergy Immunotherapy for indoor and outdoor allergens, or thelike. Additionally, amikacin, gentamicin, tobramicin, rifabutin,rifapentine, sparfloxacin, ciprofloxacin, quinolones, azithromycin,erythromycin, isoniazid, or the like, can be considered to be useful.

According to embodiments of the invention preferred, β₂ agonists in thecombinations according to the invention are selected from the groupconsisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol,clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, TD3327, ritodrine, salmeterol, salmefamol, soterenot, sulphonterol,tiaramide, terbutaline, and tolubuterol.

Additive

The additive according to embodiments of the present invention has twoparts. One part is hydrophilic and the other part is a drug affinitypart. The drug affinity part is a hydrophobic part, and/or has anaffinity to the therapeutic agent by hydrogen bonding and/or van derWaals interactions. The drug affinity part of the additive may bind thehydrophobic or lipophilic drug, such as rapamycin or paclitaxel, withwhich they share structural similarities, and lipids of cell membranes.The hydrophilic portion accelerates diffusion and increases permeationof the drug into tissue. In some embodiments, such as coatings formedical devices, the additive may facilitate rapid movement of drug offa medical device during deployment at the target site by preventinghydrophobic drug molecules from clumping to each other and to thedevice, increasing drug solubility in interstitial spaces, and/oraccelerating drug passage through polar head groups to the lipid bilayerof cell membranes of target tissues.

The additive according to embodiments of the present invention has adrug affinity part and a hydrophilic part. The drug affinity part is ahydrophobic part and/or has an affinity to the therapeutic agent byhydrogen bonding and/or van der Waals interactions. The hydrophobic partmay include aliphatic and aromatic organic hydrocarbon compounds, suchas benzene, toluene, and alkanes, among others. These parts are notwater soluble. They may bind both hydrophobic drug, with which theyshare structural similarities, and lipids of cell membranes. They haveno covalently bonded iodine. The drug affinity part may includefunctional groups that can form hydrogen bonds with drug and withitself. The hydrophilic part may include hydroxyl groups, amine groups,amide groups, carbonyl groups, carboxylic acid and anhydrides, ethyloxide, ethyl glycol, polyethylene glycol, ascorbic acid amino acid,amino alcohol, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic salts and their substituted molecules,among others. Hydroxyl, carboxyl, acid, amide or amine groups, forexample, may be advantageous since they easily displace water moleculesthat are hydrogen-bound to polar head groups and surface proteins ofcell membranes and may function to remove this barrier betweenhydrophobic drug and cell membrane lipid. These parts can dissolve inwater and polar solvents. These additives are not oils, lipids, orpolymers. The therapeutic agent is not enclosed in micelles or liposomesor encapsulated in polymer particles. The additive of embodiments of thepresent invention have hydrophobic and hydrophilic components to bothbind drug and facilitate its rapid movement off a medical device duringdeployment and into target tissues.

The additives in embodiments of the present invention are surfactantsand chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties. The surfactants include ionic,nonionic, aliphatic, and aromatic surfactants. The chemical compoundswith one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide orester moieties are amino alcohols, hydroxyl carboxylic acid andanhydrides, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, and their substitutedmolecules.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties as well as non-polar hydrophobic (lipophilic)moieties.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5are typically more membrane permeable. For purposes of certainembodiments of the present invention, it is preferable that the additivehas log P less than log P of the drug to be formulated (as an example,log P of paclitaxel is 7.4). A greater log P difference between the drugand the additive can facilitate phase separation of drug. For example,if log P of the additive is much lower than log P of the drug, theadditive may accelerate the release of drug in an aqueous environmentfrom the surface of a device to which drug might otherwise tightlyadhere, thereby accelerating drug delivery to tissue. In certainembodiments of the present invention, log P of the additive is negative.In other embodiments, log P of the additive is less than log P of thedrug. While a compound's octanol-water partition coefficient P or log Pis useful as a measurement of relative hydrophilicity andhydrophobicity, it is merely a rough guide that may be useful indefining suitable additives for use in embodiments of the presentinvention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical excipients, natural products and derivatives thereof(such as sugars, vitamins, amino acids, peptides, proteins, and fattyacids), low molecular weight oligomers, surfactants (anionic, cationic,non-ionic, and ionic), and mixtures thereof. The following detailed listof additives useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of theinvention, as are combinations of surfactant and other additives.Surfactants often have one or more long aliphatic chains such as fattyacids that may insert directly into the lipid bilayers of cell membranesto form part of the lipid structure of the cells, while other componentsof the surfactants loosen the lipid structure and enhance drugpenetration and absorption. The contrast agent, such as iopromide, doesnot have these properties.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10.

It should be understood that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions, for example. For many importantsurfactants, including several polyethoxylated surfactants, it has beenreported that HLB values can differ by as much as about 8 HLB units,depending upon the empirical method chosen to determine the HLB value(Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping theseinherent difficulties in mind, and using HLB values as a guide,surfactants may be identified that have suitable hydrophilicity orhydrophobicity for use in embodiments of the present invention, asdescribed herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Preferred hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Most preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. TheHLB values are in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters.

Polyethylene Glycol Glycerol Fatty Acid Esters

Preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, andPEG-30 glyceryl oleate.

Alcohol-Oil Transesterification Products

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,preferred hydrophilic surfactants are PEG-35 castol oil (Incrocas 35),PEG 40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate(TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil(Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil(Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-5 hydrogenated castoroil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6caprylic/capric glycerides (Softigen 767). Preferred hydrophobicsurfactants in this class include PEG-6 corn oil (Labrafil® M 2125 CS),PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS),PEG-6 triolein (Labrafil®b M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides(Crovol A40).

Polyglyceryl Fatty Acids

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, preferred hydrophobic surfactants include polyglyceryloleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO),polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate. Preferred hydrophilic surfactants include polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-0), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860),polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.Polyglyceryl polyricinoleates (Polymuls) are also preferred surfactants.

Propylene Glycol Fatty Acid Esters

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,preferred hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800).

Sterol and Sterol Derivatives

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Preferred derivatives include thepolyethylene glycol derivatives. A preferred surfactant in this class isPEG-24 cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, preferred surfactants includePEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitanmonooleate (Tween-80). In some embodiments, laurate esters are preferredbecause they have a short lipid compared with oleate esters, increasingdrug absorption.

Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Preferredethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30).

Sugar and its Derivatives

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Preferred surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, and are suitable for use in embodiments of the presentinvention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula: HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denote the numberof polyoxyethylene and polyoxypropylene units, respectively.

Preferred hydrophilic surfactants of this class include Poloxamers 108,188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants inthis class include Poloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, preferredhydrophobic surfactants include sorbitan monolaurate (Arlacel 20),sorbitan monopalmitate (Span-40), and sorbitan monooleate (Span-80),sorbitan monostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). And second, when the pH increases so asto convert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Preferred ionic surfactants include quaternaryammonium salts, fatty acid salts and bile salts. Specifically, preferredionic surfactants include benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate.These quaternary ammonium salts are preferred additives. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Chemical Compounds with One or More Hydroxyl, Amino, Carbonyl, Carboxyl,Acid, Amide or Ester Moieties

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties include amino alcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sugars, glucose,sucrose, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acids, and their substituted molecules. Hydrophilic chemicalcompounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide, or ester moieties having a molecular weight less than5,000-10,000, are preferred in certain embodiments. In otherembodiments, molecular weight of the additive with one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide, or ester moieties is preferablyless than 1000-5,000, or more preferably less than 700-1,000, or mostpreferably less than 750. In these embodiments, molecular weight of theadditive is preferred to be less than that of the drug to be delivered.Further, in some embodiments, the molecular weight of the additive ispreferred to be higher than 80 since molecules with molecular weightless than 80 very easily evaporate and do not stay in coatings of amedical device. Small molecules can diffuse quickly. They can releasethemselves easily from the delivery balloon, accelerating release ofdrug, and they can diffuse away from drug when the drug binds tissue ofthe body lumen.

In certain embodiments, for example, in a coating for a medical device,more than four hydroxyl groups are preferred, for example in the case ofa high molecular weight additive. Large molecules diffuse slowly. If themolecular weight of the additive or the chemical compound is high, forexample if the molecular weight is above 800, above 1000, above 1200,above 1500, or above 2000; large molecules may elute off of the surfaceof a medical device too slowly to release drug under 2 minutes. If theselarge molecules contain more than four hydroxyl groups they haveincreased hydrophilic properties, which is necessary for relativelylarge molecules to release drug quickly. The increased hydrophilicityhelps elute the coating off the balloon, accelerates release of drug,and improves or facilitates drug movement through water barrier andpolar head groups of lipid bilayers to penetrate tissues. The hydroxylgroup is preferred as the hydrophilic moiety because it is unlikely toreact with water insoluble drug, such as paclitaxel or rapamycin. Insome embodiments, the chemical compound having more than four hydroxylgroups has a melting point of 120° C. or less. In some embodiments, thechemical compound having more than four hydroxyl groups has threeadjacent hydroxyl groups that in stereo configuration are all on oneside of the molecule. For example, sorbitol and xylitol have threeadjacent hydroxyl groups that in stereoconfiguration are all on one sideof the molecule, while galactitol does not. The difference impacts thephysical properties of the isomers such as the melting temperature. Thestereoconfiguration of the three adjacent hydroxyl groups may enhancedrug binding. This will lead to improved compatibility of the waterinsoluble drug and hydrophilic additive, and improved tissue uptake andabsorption of drug.

Some of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein are very stableunder heating. They survive an ethylene oxide sterilization process anddo not react with the water insoluble drug paclitaxel or rapamycinduring sterilization. L-ascorbic acid and its salt and diethanolamine,on the other hand, do not necessarily survive such a sterilizationprocess, and they react with paclitaxel. A different sterilizationmethod is therefore preferred for L-ascorbic acid and diethanolamine.Hydroxyl, ester, and amide groups are preferred because they areunlikely to react with therapeutic agents such as paclitaxel orrapamycin. Sometimes, amine and acid groups do react with paclitaxel,for example, experimentally, benzoic acid, gentisic acid,diethanolamine, and ascorbic acid were not stable under ethylene oxidesterilization, heating, and aging process and reacted with paclitaxel.When the chemical compounds described herein are formulated withpaclitaxel, a top coat layer may be advantageous in order to preventpremature drug loss during the device delivery process before deploymentat the target site, since hydrophilic small molecules sometimes releasedrug too easily. The chemical compounds herein rapidly elute drug offthe balloon during deployment at the target site. Surprisingly, eventhough some drug is lost during transit of the device to the target sitewhen the coating contains these additives, experimentally drugabsorption by tissue is unexpectedly high after only 0.2-2 minutes ofdeployment, for example, with the additive hydroxyl lactones such asribonic acid lactone and gluconolactone.

Fat-Soluble Vitamins and Salts Thereof

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to these anumber of other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention.

The following examples of fat-soluble vitamin derivatives and/or sourcesare also useful as additives: Alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II). Folic acid is also of this type, and although it iswater-soluble at physiological pH, it can be formulated in the free acidform. Other derivatives of fat-soluble vitamins useful in embodiments ofthe present invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and their Amphiphilic Derivatives

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cycothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and their Salts

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and their derivatives are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has solubilityin unbuffered water of less than about 4% (40 mg/ml). These includeCystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful, such as dopamine hydrochloride, DOPA, LOVADOPA, and carbidopa.Through simple reactions well known in the art hydrophilic molecules maybe joined to hydrophobic amino acids, or hydrophobic molecules tohydrophilic amino acids, to make additional additives useful inembodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides, Peptides and Proteins

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a particularly preferredadditive since it is water soluble and contains significant hydrophobicparts to bind drug: paclitaxel is 89% to 98% protein-bound after humanintravenous infusion, and rapamycin is 92% protein bound, primarily(97%) to albumin. Furthermore, paclitaxel solubility in PBS increasesover 20-fold with the addition of BSA. Albumin is naturally present athigh concentrations in serum and is thus very safe for humanintravascular use.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and their Esters and Anhydrides

Examples are acetic acid and anhydride, benzoic acid and anhydride,acetylsalicylic acid, diflunisal, 2-hydroxyethyl salicylate,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethyl acetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water soluble and can effectively carry the drugsoff the device into the vessel walls.

Other Chemical Compounds with One or More Hydroxyl, Amine, Carbonyl,Carboxyl, or Ester Moieties

The additives according to embodiments include amino alcohols, alcohols,amines, acids, amides and hydroxyl acids in both cyclo and linearaliphatic and aromatic group. Examples are L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactrone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,gulonic acid lactone, mannoic lactone, erythronic acid lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol,sorbitol, glucose, sucrose, lactose, maltose, ribose, arabinose, lyxose,xylose, fructose, mannose, glucitol, sugars, sugar phosphates,glucopyranose phosphate, sugar sulphates, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, xylitol, 2-ethoxyethanol,cyclodextrin, (2-hydroxypropyl)cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described, polyglycidol, glycerol,multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol),tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol)oligomers, di(propylene glycol), tri(propylene glycol), tetra(propyleneglycol, and penta(propylene glycol), poly(propylene glycol) oligomers, ablock copolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof

Combinations of additives are also useful for purposes of the presentinvention.

One embodiment comprises the combination or mixture of two additives,for example, a first additive comprising a surfactant and a secondadditive comprising a chemical compound with one or more hydroxyl,amine, carbonyl, carboxyl, or ester moieties.

The combination or mixture of the surfactant and the small water-solublemolecule (the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) has advantages. Formulationscomprising mixtures of the two additives with water-insoluble drug arein certain cases superior to mixtures including either additive alone.The hydrophobic drugs bind extremely water-soluble small molecules morepoorly than they do surfactants. The water-insoluble drug has Log Phigher than both that of the surfactant and that of small water-solublemolecules. However, Log P of the surfactant is typically higher than LogP of the chemical compounds with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties. The surfactant has a relatively high Log P(usually above 0) and the water soluble molecules have low Log P(usually below 0). Some surfactants, when used as additives inembodiments of the present invention, such as in coatings of medicaldevices, adhere so strongly to the water-insoluble drug and the surfaceof the medical device that drug is not able to rapidly release from thesurface of the medical device at the target site. On the other hand,some of the water-soluble small molecules (with one or more hydroxyl,amine, carbonyl, carboxyl, or ester moieties) adhere so poorly to themedical device that they release drug before it reaches the target site,for example, into serum during the transit of a coated balloon catheterto the site targeted for intervention. Surprisingly, by adjusting theratio of the concentrations of the small hydrophilic molecule and thesurfactant in the formulation, the inventor has found that the coatingstability during transit and rapid drug release when inflated andpressed against tissues of the lumen wall at the target site oftherapeutic intervention in certain cases is superior to a formulationcomprising either additive alone. Furthermore, the miscibility andcompatibility of the water-insoluble drug and the highly water-solublemolecules is improved by the presence of the surfactant. The surfactantalso improves coating uniformity and integrity by its good adhesion tothe drug and the small molecules. The long chain hydrophobic part of thesurfactant binds drug tightly while the hydrophilic part of thesurfactant binds the water-soluble small molecules.

The surfactants in the mixture or the combination include all of thesurfactants described herein for use in embodiments of the invention.The surfactant in the mixture may be chosen from PEG fatty esters, PEGomega-3 fatty esters and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters, Tween 20, Tween 40, Tween 60,p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, Tween 20, Tween 40, Tween 60, Tween 80,octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside and theirderivatives.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture or the combination includeall of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein for use inembodiments of the invention. The chemical compound with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties in the mixturehas at least one hydroxyl group in one of the embodiments in theinventions. In certain embodiments, more than four hydroxyl groups arepreferred, for example in the case of a high molecular weight additive.In some embodiments, the chemical compound having more than fourhydroxyl groups has a melting point of 120° C. or less. Large moleculesdiffuse slowly. If the molecular weight of the additive or the chemicalcompound is high, for example if the molecular weight is above 800,above 1000, above 1200, above 1500, or above 2000; large molecules mayelute off of the surface of the medical device too slowly to releasedrug under 2 minutes. If these large molecules contain more than fourhydroxyl groups they have increased hydrophilic properties, which isnecessary for relatively large molecules to release drug quickly. Theincreased hydrophilicity helps elute the coating off the balloon,accelerates release of drug, and improves or facilitates drug movementthrough water barrier and polar head groups of lipid bilayers topenetrate tissues. The hydroxyl group is preferred as the hydrophilicmoiety because it is unlikely to react with water insoluble drug, suchas paclitaxel or rapamycin.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture is chosen from L-ascorbicacid and its salt, D-glucoascorbic acid and its salt, tromethamine,triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols,glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone,gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,gulonic acid lactone, mannoic lactone, erythronic acid lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol,sorbitol, glucitol sugar phosphates, glucopyranose phosphate, sugarsulfates, sinapic acid, vanillic acid, vanillin, methyl paraben, propylparaben, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, ribose,mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose,cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described above, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

Mixtures or combinations of a surfactant and a water-soluble smallmolecule confer the advantages of both additives. The water insolubledrug often has a poor compatibility with highly water-soluble chemicalcompounds, and the surfactant improves compatibility. The surfactantalso improves the coating quality, uniformity, and integrity, andparticles do not fall off the balloon during handling. The surfactantreduces drug loss during transit to a target site. The water-solublechemical compound improves the release of drug off the balloon andabsorption of the drug in the tissue. Experimentally, the combinationwas surprisingly effective at preventing drug release during transit andachieving high drug levels in tissue after very brief 0.2-2 minutedeployment. Furthermore, in animal studies it effectively reducedstenosis and late lumen loss.

Some of the mixtures or combinations of surfactants and water-solublesmall molecules are very stable under heating. They survived an ethyleneoxide sterilization process and do not react with the water insolubledrug paclitaxel or rapamycin during sterilization. The hydroxyl, ester,amide groups are preferred because they are unlikely to react withtherapeutic agents such as paclitaxel or rapamycin. Sometimes amine andacid groups do react with paclitaxel and are not stable under ethyleneoxide sterilization, heating, and aging. When the mixtures orcombinations described herein are formulated with paclitaxel, a top coatlayer may be advantageous in order to protect the drug layer and frompremature drug loss during the device.

Preferred additives include p-isononylphenoxypolyglycidol, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryloleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine (amino acids); cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid and its salt,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.(chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, or ester moieties). Some of these additives are bothwater-soluble and organic solvent-soluble. They have good adhesiveproperties and adhere to the surface of polyamide medical devices, suchas balloon catheters. They may therefore be used in the adherent layer,top layer, and/or in the drug layer of embodiments of the presentinvention. The aromatic and aliphatic groups increase the solubility ofwater insoluble drugs in the coating solution, and the polar groups ofalcohols and acids accelerate drug permeation of tissue.

Other preferred additives in embodiments of the invention include thecombination of a surfactant and a chemical compounds with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties. Examples areTween 20/sorbitol, Tween 20/glucose, Tween 20/sucrose, Tween20/lactobionic acid, Tween 20/gluconolactone, Tween 20/meglumine/lacticacid, Tween 20/meglumine/gentisic acid, Tween 80/sorbitol, Tween80/glucose, Tween 80/sucrose, Tween 80/lactobionic acid, Tween80/gluconolactone, Tween 80/meglumine/lactic acid, Tween80/meglumine/gentisic acid, N-octanoyl N-methylglucamine/sorbitol,N-octanoyl N-methylglucamine/glucose, N-octanoylN-methylglucamine/sucrose, N-octanoyl N-methylglucamine/lactobionicacid, N-octanoyl N-methylglucamine/gluconolactone, N-octanoylN-methylglucamine/meglumine/lactic acid, and N-octanoylN-methylglucamine/meglumine/gentisic acid.

Other preferred additives according to embodiments of the inventioninclude the combination or mixture or amide reaction products of anamino alcohol and an organic acid. Examples are lysine/glutamic acid,lysine acetate, lactobionic acid/meglumine, lactobionicacid/tromethanemine, lactobionic acid/diethanolamine, lacticacid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine,gentisic acid/meglumine, gentisic acid/tromethanemine, gensiticacid/diethanolamine, vanillic acid/meglumine, vanillicacid/tromethanemine, vanillic acid/diethanolamine, benzoicacid/meglumine, benzoic acid/tromethanemine, benzoicacid/diethanolamine, acetic acid/meglumine, acetic acid/tromethanemine,and acetic acid/diethanolamine.

Other preferred additives according to embodiments of the inventioninclude hydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxylester, and hydroxyl amide. Examples are gluconolactone,D-glucoheptono-1, 4-lactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, erythronic acid lactone, ribonic acid lactone,glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lacticacid, acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid,methyl paraben, propyl paraben, and derivatives thereof.

Other preferred additives include n-octyl-β-D-glucopyranoside,octoxynol-9 (Triton X-100), Polysorbates (such as 20, 21, 40, 60, 80 and81), Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol(Olin-10 G and Surfactant-10G), PEG glyceryl monooleate, sorbitanmonolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitanmonooleate (Span-80), sorbitan monostearate, polyglyceryl-10 oleate,polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10stearate, L-ascorbic acid, thiamine, maleic anhydride, niacinamide,2-pyrrolidone-5-carboxylic acid, and the like. These additives are bothwater soluble and organic solvent soluble. They have good adhesiveproperties and adhere to the surface of polyamide medical devices, suchas balloon catheters. They may therefore be used in both the adherentlayer and in the drug layer of embodiments of the present invention. Thearomatic and aliphatic groups increase the solubility of water insolubledrugs in the coating solution, and the polar groups of alcohols andacids accelerate drug permeation of tissue.

Other preferred additives that may be useful in embodiments of thepresent invention include riboflavin, riboflavin-phosphate sodium,Vitamin D3, folic acid (vitamin B9), vitamin 12,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. They may form hydrogen bonds and van der Waalsinteractions with drug. Compounds containing one or more hydroxyl,carboxyl, or amine groups, for example, are especially useful asadditives because these additives have a good affinity to the vesselwall. These molecules are polyglyceryl fatty esters, ascorbic ester offatty acids, sugar ester, alcohol and ether of fatty acids. The fattychains can insert into the lipid structure of target tissue membranescarrying drug to lipid structures. Some of the amino acids, vitamins andorganic acids have aromatic C═N groups as well as amino, hydroxyl, andcarboxylic components to their structure. These structure can bind orcomplex with hydrophobic drug, such as paclitaxel or rapamycin, and theyalso have structural parts that facilitate tissue penetration byremoving barriers between hydrophobic drug and lipid structure of cellmembranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity to the vessel wall and can displacehydrogen bound water molecules. At the same time they have long chainsof fatty acid, alcohol, ether and ester that can both complex withhydrophobic drug and integrate into the lipid structure of the cellmembranes to form the part of the lipid structure. This deformation orloosening of the lipid membrane of target cells may further acceleratepermeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid, all have a very highwater and ethanol solubility and a low molecular weight and small size;therefore they can penetrate into the tissue easily. They also havestructural components including aromatic C═N, amino, hydroxyl, andcarboxylic groups. These structures have very good compatibility withpaclitaxel and rapamycin and can increase the solubility of thewater-insoluble drugs in water and enhance their absorption intotissues.

Representative examples of additives include cetyl pyridinium chloride,gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia,cholesterol, tragacanth, stearic acid, calcium stearate, glycerolmonostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol etherssuch as cetomacrogol 1000), polyoxyethylene sorbitan fatty acid esters(e.g., the commercially available Tweens® such as e.g., Tween 20® andTween 80® (ICI Specialty Chemicals)); polyethylene glycols (e.g.,Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)), dodecyltrimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicondioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulosecalcium, hydroxypropyl cellulose (HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),polyvinylpyrrolidone (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde (also known as tyloxapol,superione, and triton), poloxamers (e.g., Pluronics F68® and F108®,which are block copolymers of ethylene oxide and propylene oxide);poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, whichis a tetrafunctional block copolymer derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (BASF WyandotteCorporation, Parsippany, N.J.)); a charged phospholipid such asdimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic1508® (T-1508) (BASF Wyandotte Corporation), dialkylesters of sodiumsulfosuccinic acid (e.g., Aerosol OT®, which is a dioctyl ester ofsodium sulfosuccinic acid (American Cyanamid)); Duponol P®, which is asodium lauryl sulfate (DuPont); Tritons X-200®, which is an alkyl arylpolyether sulfonate (Rohm and Haas); Crodestas F-110®, which is amixture of sucrose stearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-1OG® or Surfactant10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.);and SA9OHCO, which is C₁₈H₃₇CH₂(CON(CH₃)CH₂(CHOH)₄(CH₂OH)₂ (EastmanKodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside;n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-μ-D-glucopyranoside; octyl β-D-thioglucopyranoside; and thelike. Tyloxapol is a particularly preferred additive for the pulmonaryor intranasal delivery of steroids, even more so for nebulizationtherapies.

Some of the additives are characterized by rapid extracellulardistribution followed by renal excretion by glomerular filtration. Ithas been reported (Topic in Current Chemistry, Vol. 222, P 150) thatthese additives are extravasated to a massive extent on the first passand extraction of the nonionic additives averaged 33% in normallyperfused myocardial area and 50% in stenotic area. In another model,approximately 80% of the myocardial content of I-iothalamate was foundin the extravascular space 1 minute after intravenous injection in rats.

Some of the X-ray contrast agents can be used as the additives inembodiments of the invention. Iodinated contrast agents are widely usedin X-ray diagnostic procedure such as angiography, urography andcomputed tomography. X-ray contrast agents have been moved historicallyfrom inorganic iodide, to organic mono-iodine compounds (Uroselectan A),bis-iodine (Uroselectan B) and tris-iodine substances (diatrizoate),from lipophilic to hydrophilic agents from ionic (diatrizoate) tonon-ionic drugs (iopromide) and from monomers (iopromide) to dimmers(iotrolan).

All presented available X-ray contrast agents for intravascularinjection are based upon the triiodobenzene ring substituted with two orthree additional hydrophilic groups. In the case of biliary contrastagents (compounds that are taken up by the liver and excreted mainly bythe biliary tract), two hydrophilic groups are introduced. Forangiographic/urographic agents (compounds that stay within theextravascular distribution volume and that are excreted by the kidneys),three hydrophilic groups are introduced. The monomers are exclusivelyderived from aminoisophathalic acid. They only differ by theirside-chains, which determine their physiochemical characteristics suchas solubility, hydrophilicity, viscosity and osmolality. The aqueoussolubility of X-ray contrast agents is generally extremely high being inthe order of 1000 mg/ml. Most preparations of X-ray contrast agents areover-saturated solutions.

The relative amount of drug and additive can vary widely and the optimalamount of the additive can depend upon, for example, the particular drugand additives selected, the critical micelle concentration of theadditive if it forms micelles, the hydrophilic-lipophilic-balance (HLB)of the additive, the melting point of the additive, the water solubilityof the additive and/or drug, the surface tension of water solutions ofthe additive, etc.

In embodiments of the present invention, the optimal ratio of drug toadditive is about 1% to about 99% drug, more preferably about 30% toabout 90% drug.

Adherent Layer

The adherent layer, which is an optional layer underlying the drugcoating layer, improves the adherence of the drug coating layer to theexterior surface of the medical device, such as a balloon catheter orstent, and protects coating integrity. If drug and additive differ intheir adherence to the medical device, the adherent layer may preventdifferential loss (during transit) or elution (at the target site) ofdrug layer components in order to maintain consistent drug-to-additiveratio delivery at the target site of therapeutic intervention.Furthermore, the adherent layer may function to facilitate release ofcoating layer components which otherwise might adhere too strongly tothe device for elution during brief contact with tissues at the targetsite. For example, in the case where a particular drug binds the medicaldevice tightly, more hydrophilic components are incorporated into theadherent layer in order to decrease affinity of the drug to the devicesurface.

The adherent layer comprises a polymer or an additive or mixtures ofboth. The polymers that are useful for forming the adherent layer areones that are biocompatible and avoid irritation of body tissue. Someexamples of polymers that are useful for forming the adherent layer arepolymers that are biostable, such as polyurethanes, silicones, andpolyesters. Other polymers that are useful for forming the adherentlayer include polymers that can be dissolved and polymerized on themedical device.

Some examples of polymers that are useful in the adherent layer ofembodiments of the present invention include polyolefins,polyisobutylene, ethylene-α-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, Nylon 12 andits block copolymers, polycaprolactone, polyoxymethylenes, polyethers,epoxy resins, polyurethanes, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, chitins,polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxidecopolymers, polyethylene glycol, polypropylene glycol, polyvinylalcohol, and mixtures and block copolymers thereof.

Since medical devices such as balloon catheters and stents undergomechanical manipulation, i.e., expansion and contraction, examples ofpolymers that are useful in the adherent layer include elastomericpolymers, such as silicones (e.g., polysiloxanes and substitutedpolysiloxanes), polyurethanes, thermoplastic elastomers, ethylene vinylacetate copolymers, polyolefin elastomers, and EPDM rubbers. Due to theelastic nature of these polymers, when these polymers are used, thecoating better adheres to the surface of the medical device when thedevice is subjected to forces or stress.

The adherent layer may also comprise one or more of the additivespreviously described, or other components, in order to maintain theintegrity and adherence of the coating layer to the device and tofacilitate both adherence of drug and additive components during transitand rapid elution during deployment at the site of therapeuticintervention.

Top Layer

In order to further protect the integrity of the drug layer, an optionaltop layer may be applied to prevent loss of drug during transit throughtortuous anatomy to the target site or during the initial expansion ofthe device before the coating makes direct contact with target tissue.The top layer may release slowly in the body lumen while protecting thedrug layer. The top layer will erode more slowly if it is comprised ofmore hydrophobic, high molecular weight additives. Surfactants areexamples of more hydrophobic structures with long fatty chains, such asTween 20 and polyglyceryl oleate. High molecular weight additivesinclude polyethylene oxide, polyethylene glycol, and polyvinylpyrrolidone. Hydrophobic drug itself can act as a top layer component.For example, paclitaxel or rapamycin are hydrophobic. They can be usedin the top layer. On the other hand, the top layer cannot erode tooslowly or it might actually slow the release of drug during deploymentat the target site. Other additives useful in the top coat includeadditives that strongly interact with drug or with the coating layer,such as p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryloleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In asthma and COPD, many of the clinical signs and symptoms are due toairway obstruction resulting from smooth muscle constriction. Themagnitude of the obstructive response observed for a given degree ofsmooth muscle activation reflects the contractile capacity of the airwaysmooth muscle and the resistance to airway deformation. The airwaysmooth muscle plays a central role in asthma. The luminal folding orbuckling as a consequence of airway smooth muscle constriction has beenobserved in asthma. Such bucking has also been observed in arteries,blood vessels in the myocardium, and the gastrointestinal tract (J.Appl. Physiol. 83(6): 1814-1821, 1977). Studies also show that airwaysmooth muscle cell, in addition to its contractile function, canparticipate in and coordinate the inflammatory response. Theinflammatory smooth muscle produces excess thick and sticky mucus, whichcauses asthma attack by blocking airways. The smooth muscle hyperplasiahas been linked to airway hyper responsiveness that is a criticalphenotypic characteristic of asthma.

The causes of the coronary heart diseases and asthma may be theneointimal proliferation of smooth muscle in arterial vessels and inwalls of airways. The one aspect of the invention is to deliverpaclitaxel or rapamycin and their analogues to the wall of airways totreat the asthma. The drug coated stents with the two drugs have beenapproved for inhibiting the growth of the smooth muscle cells invascular arterial vessels. Drug coated balloon has been approved toachieve similar results as the drug coated stent. Therefore, the drugcoated stent and drug coated balloon used for vascular diseases can beadapted in the obstructive airway for the treatment of asthma. Themethod comprises inserting the therapeutic-agent-delivery ballooncatheter into the airway in the lung, inflating the balloon catheter,releasing drug to an airway wall of an airway such that a diameter ofthe airway is increased, deflating the balloon, withdrawing the ballooncatheter from the airway. The drug may be released to the airway wallprior to, during, or after an asthma attack. The drug may be released inan amount sufficient to temporarily or permanently increase the diameterof the airway. The method may be performed while the airway is open,closed, or partially closed.

The pulmonary balloon catheters and stents are similar to vascularballoon catheters and stents. The diameters of the pulmonary ballooncatheters and stents are 8, 10, 12, 14, 16, 18, 20, 22 mm with lengthsof 20, 30, 40, 50, 60, 70, 80 mm. It is designed to pass over a 0.035 inguide wire through its guide wire lumen. The balloon can also be passedthrough a minimum 5.0 mm working channel bronchoscope. The diameters ofthe sinus balloon catheters are 2.0, 3.0, 3.0, 4.0 mm and 10 mm withlengths of 10, 12, 15, 18, 20, and 30 mm.

The paclitaxel or rapamycin and their analogues can be used fortreatments of respiratory disorders such as asthma, chronic obstructivepulmonary disease and chronic sinusitis. A method of treatingrespiratory disorders comprises administrating an anti-proliferate andanti-inflammatory effective amount of rapamycin, or paclitaxel or theiranalogues to said mammal orally, parenterally, intravascularly,intranasally, intrabronchially, transdermally, rectally, or via animpregnated vascular stent or balloon catheters.

The paclitaxel or rapamycin and their analogues can be used incombinations with inhaled corticosteroids, inhaled atrovent, inhaledleukotriene inhibitors, and inhaled epinephrine, long acting & selectivebeta agonists for treatments of asthma and COPD. A method of treatingasthma and COPD in the lung comprises administrating an anti-proliferateand anti-inflammatory effective amount of rapamycin, or paclitaxel ortheir analogues in combinations with inhaled corticosteroids, inhaledatrovent, inhaled leukotriene inhibitors, inhaled epinephrine, longacting & selective beta agonists to said mammal orally, parenterally,intravascularly, intranasally, intrabronchially, transdermally,rectally, or via an impregnated vascular stent or balloon catheters.

Embodiments of the present invention also pertain to a method fortreating the disease state, especially nasal and sinus dysplasia inmammals caused by mammalian nasal and sinus cells involved in theinflammatory response and compositions useful in the method. The methodfor treating the disease state in mammals caused by mammalian nasal andsinus cells involved in the inflammatory response comprises: contactingthe mammalian nasal and sinus cells participating in the inflammatoryresponse with the anti-proliferate and anti-inflammatory drugs.

Embodiments of the present invention also pertain to compositions forreducing and treating the disease state in mammals caused by undesiredinflammatory response of nasal and sinus cells comprising ananti-proliferate and anti-inflammatory drug a carrier, and an additivecomposition, wherein the drugs are paclitaxel, rapamycin and theiranalogues.

In a preferred embodiment, the therapeutic compositions are administeredby nasal inhalation. In another preferred embodiment, the therapeuticcompositions are administered by nose drops. The therapeuticcompositions may be first nebulized by any suitable means. Thetherapeutic compositions may be in liquid or solid form with liquiddroplets or particle size being small enough to facilitate access tonasal and sinus tissue by inhalation or nose drops.

In one embodiment, the ratio by weight of the additive to thetherapeutic agent in the layer is from about 0.05 to 100, for example,from about 0.1 to 5, from 0.5 to 2, and further for example, from about0.8 to 1.2.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

EXAMPLES

The following examples include embodiments of formulations and medicaldevice coating layers within the scope of the present invention. Theexamples presented here are all vascular applications. The pathologicalstructure of blood vessels and airway and sinus lumen are very similar.All of the layer structure and cell types are very similar as well. Thedrug formulation, device and drug absorption can be applied in thetreatment of asthma, chronic obstructive pulmonary disease, and chronicsinusitis. While the following examples are considered to embody thepresent invention, the examples should not be interpreted as limitationsupon the present invention.

Example 1 Preparation of Coating Solutions

Formulation 1—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol),25-100 mg ascorbyl palmitate, 25-100 mg L-ascorbic acid and 0.5 mlethanol were mixed.

Formulation 2—

50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol),50-200 mg polyglyceryl-10 oleate and 0.5 ml ethanol were mixed.

Formulation 3—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol),50-200 mg octoxynol-9 and 0.5 ml ethanol were mixed.

Formulation 4—

50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol),50-200 mg p-isononylphenoxypolyglycidol and 0.5 ml ethanol were mixed.

Formulation 5—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol),50-200 mg Tyloxapol and 0.5 ml ethanol was mixed.

Formulation 6—

50-150 mg (0.05-0.16 mmole) rapamycin in 2-6 ml acetone (or ethanol),50-150 mg L-ascorbic acid in 1 ml water or ethanol, both, then weremixed.

Formulation 7—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol),50-150 mg niacinamide in 1 ml water or ethanol, and both were mixed.

Formulation 8—

50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol),50-200 mg nicotinic acid in 1 ml water or ethanol and both were mixed.

Formulation 9—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml ethanol (or acetone), 150mg thiamine hydrochloride in 1 ml water, and 0.5 ml both were mixed.

Formulation 10—

50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone or ethanol, 150 mg2-pyrrolidone-5-carboxylic acid in 1 ml water or ethanol, and both weremixed.

Formulation 11—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75mg p-isononylphenoxypolyglycidol, 75 mg niacinamide in 1 ml water orethanol, and 0.5 ml ethanol were mixed.

Formulation 12—

50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (or ethanol), 75mg Octoxynol-9, 75 mg thiamine hydrochloride in 1 ml water or ethanol,and 0.5 ml ethanol were mixed.

Formulation 13—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75mg p-isononylphenoxypolyglycidol, 75 mg 2-pyrrolidone-5-carboxylic acidin 1 ml water or ethanol, and 0.5 ml ethanol were mixed.

Formulation 14—

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75mg p-isononylphenoxypolyglycidol, 75 mg nicotinic acid in 1 ml water orethanol, and 0.5 ml ethanol were mixed.

Formulation 15

50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (or ethanol), 75mg p-isononylphenoxypolyglycidol, 75 mg L-ascorbic acid in 1 ml water orethanol, and 0.5 ml ethanol were mixed.

Formulation 16

50-150 mg (0.06-0.18 mmole) paclitaxel was dissolved in 5-10 mlmethylene chloride. The solution was added to 30 ml of human serumalbumin solution (5% w/v). The solution was then homogenized for 5minutes at low speed to form an emulsion. The emulsion was thensonicated at 40 kHz at 50-90% power at 0 to 5 degrees C. for 1 to 5 min.

Formulation 17—

50-150 mg (0.05-0.16 mmole) rapamycin was dissolved in 5-10 ml methylenechloride and 10-30 mg p-isononylphenoxypolyglycidol. The solution wasadded to 30 ml of human serum albumin solution (5% w/v). The solutionwas then homogenized for 5 minutes at low speed to form an emulsion. Theemulsion was then sonicated at 40 kHz at 50-90% power at 0 to 5° C. for1 to 5 min.

Formulation 18—

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, and 50-200 mg gluconolactone were mixed.

Formulation 19—

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 mlethanol, 35-70 mg Tween 20, and 35-70 mg N-octanoyl N-methylglucaminewere mixed.

Formulation 20—

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-1.0 ml acetone, 0.4-1.0 mlethanol, 0.2-0.4 ml water, 35-70 mg Tween 20, and 35-70 mg sorbitol weremixed.

Formulation 21—

40-80 mg (0.048-0.096 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 mlethanol, 40-80 mg meglumine, and 32-64 mg gensitic acid (equal molarratio with meglumine) were mixed.

Formulation 22—

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 mlethanol, 0.25-0.50 ml water, 35-70 mg lactobionic acid, and 10-20 mgdiethanolamine (equal molar ratio with lactobionic acid) were mixed.

Formulation 23—

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 mlethanol, and 70-140 mg N-octanoyl N-methylglucamine were mixed.

Formulation 24—

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 mlethanol, 0.2-0.4 ml water, 35-70 mg meglumine, and 18-36 mg lactic acid(equal molar ratio with meglumine) were mixed.

Formulation 25—

50-100 mg (0.06-0.12 mmole) paclitaxel, 0.8-1.6 ml acetone, 0.8-1.6 mlethanol, 0.4-1.0 ml water, 50-100 mg gensitic acid, and 30-60 mgdiethanolamine (equal molar ratio with gensitic acid) were mixed.

Formulation 26—

Comparison solution-50 mg (0.06 mmole) paclitaxel, 1 ml ethanol, 0.2 mlacetone, 0.042 ml Ultravist 370 were mixed.

Formulation 27—

Comparison solution-40 mg (0.048 mmole) paclitaxel, 0.5 ml ethanol, 0.5ml acetone were mixed.

Formulation 28—

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 mlethanol, 35-70 mg Triton X-100, and 35-70 mg N-heptanoylN-methylglucamine were mixed.

Example 2

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) werefolded with three wings under vacuum. The folded balloon under vacuumwas sprayed or dipped in a formulation (1-17) in example 1. The foldedballoon was then dried, sprayed or dipped again, dried again, andsprayed or dipped again until sufficient amount of drug on the balloon(3 microgram per square mm) was obtained. The coated folded balloon wasthen rewrapped and sterilized for animal testing.

Example 3

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) werefolded with three wings under vacuum. The folded balloon under vacuumwas sprayed or dipped in a formulation (1-5) in example 1. The foldedballoon was then dried, sprayed or dipped again in a formulation (6-10),dried, and sprayed or dipped again until sufficient amount of drug onthe balloon (3 microgram per square mm) is obtained. The coated foldedballoon was then rewrapped and sterilized for animal testing.

Example 4

5 PTCA balloon catheters crimped with bare metal coronary stent (3 mm indiameter and 20 mm in length) were sprayed or dipped in a formulation(1-5) in example 1. The stent delivery system was then dried, sprayed ordipped again in a formulation (6-10), dried and sprayed or dipped againuntil sufficient amount of drug on the stent and balloon (3 microgramper square mm) was obtained. The coated folded stent delivery system wasthen sterilized for animal testing.

Example 5

Drug coated balloon catheters and uncoated balloon catheters (ascontrol) were inserted into coronary arteries in pigs. The balloon wasover dilated (1:1.2), and the inflated balloon was held in the vesselfor 60 seconds to release drug, then deflated and withdraw from the pig.The animals were angiographed after 3 days, 31 days, 3 months, 6 months,9 months and 12 months. The amount of drug in the artery tissues of thesacrificed animal was measured after 60 minutes, 3 days, 31 days, 3months, 6 months, 9 months and 12 months.

Example 6

5 coronary stents (3 mm in diameter and 18 mm in length) were spray ordip coated with the formulation (1-17) in example 1. The stents werethen dried, sprayed or dipped again, and dried again until a sufficientamount of drug on the stent (3 microgram per square mm) is obtained. Thecoated stent was then crimped on PTCA balloon catheters (3 mm indiameters and 20 mm in length). The coated stents with balloon catheterswere then sterilized for animal testing.

Example 7

The drug coated stent and uncoated stent (as control) were inserted intocoronary arteries in pigs, then the balloon is over dilated (1:1.2). Thestent was implanted and drug released, and the balloon is deflated andwithdraws from the pig. The animals were then angiographed after 5, 30,60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.The amount of drug in the artery tissues of the sacrificed animal wasmeasured 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9months and 12 months.

Example 8

5 PTCA balloon catheters were sprayed or dipped in the formulation(1-17) in example 1, dried, and sprayed or dipped and dried again untilsufficient amount of drug on balloon i was obtained (3 microgram persquare mm) was obtained. A bare metal coronary stent (3 mm in diameterand 20 mm in length) was crimped on each coated balloon. The coatedballoons with crimped bare metal stents was then wrapped and sterilizedfor animal test.

Example 9

5 PTCA balloon catheters were sprayed or dipped in a formulation (1-5)in example 1, dried, and sprayed or dipped again in a formulation(6-10). Balloons were then dried and sprayed or dipped again untilsufficient amount of drug on the balloon (3 microgram per square mm) wasobtained. A bare metal coronary stent (3 mm in diameter and 20 mm inlength) was crimped on each coated balloon. The coated balloons withcrimped bare metal stents were then wrapped and sterilized for animaltest.

Example 10

The drug coated balloon-expandable bare metal stent of Example 8 and 9and plain balloon-expandable bare metal stent (as control) were insertedinto coronary arteries in pigs, and the balloon is over dilated (1:1.2).Stent was implanted, and the balloon is held inflated for 60 seconds torelease drug, and the balloon was deflated and withdraw from the pig.The animals were then angiographed after 5, 30, 60 minutes, 3 days, 31days, 3 months, 6 months, 9 months and 12 months. The amount of drug inthe artery tissues of the sacrificed animal was measured after 60minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and 12months.

Example 11

150 mg (0.18 mmole) paclitaxel, 5 ml acetone (or ethyl acetate or methylethyl ketone), 150 mg acetic anhydride or maleic anhydride or diglycolicanhydride and 0.5 ml ethanol were mixed, then stirred until a solutionwas obtained. 5 PTCA balloon catheters are sprayed or dipped in thesolution, dried, and sprayed or dipped again until sufficient amount ofdrug on the balloon (3 microgram per square mm) was obtained. The coatedballoon was then treated under high pH (range pH 8-11.5) conditions tohydrolyze the anhydride. This was confirmed by IR method. Thehydrophilicity of the coating was increased. The coated balloons werethen sterilized for animal test.

Example 12

The drug coated balloon catheters and uncoated balloon catheters (ascontrol) were inserted via a bronchoscope into the pulmonary airway inpigs. The balloon was dilated, and the inflated balloon was heldexpanded in the lumen for 60 seconds to release drug. The balloon wasdeflated and withdrawn from the pig. The animals were then examinedbronchoscopically and tissues samples were taken for pathology andquantification of drug uptake after 3 days, 31 days, 3 months, 6 months,9 months and 12 months.

Example 13

The uncoated stent delivery catheters were inserted into the vascularlumen in pigs. The balloon was dilated, the stent was deployed and thedeflated balloon was then withdrawn. The pharmaceutical formulation 1-15of example 1 (10-100 ml) is injected (about 5-15 mg drug per pig) at thesite of stent implantation. The drug is then absorbed by injuriedtissue. The animals are then examined and tissues samples are taken forpathology.

Example 14

The diseased tissue (breast cancer or atheroma or stenosis) was removedsurgically from a human body. The pharmaceutical formulation 1-15 ofexample 1 (10-100 ml) was then injected into or onto the surgicalcavities created by the surgical intervention (about 5-20 mg drug). Thelocal drug delivery includes injection by long needle, guide catheters,introducer sheath, drug infusion tube and other drug delivery catheters.The drug was then absorbed by tissue at the target site.

Example 15

6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20 mm inlength) were inflated at 1-3 atm. The inflated balloon was loaded with aformulation 18-27 in example 1. The sufficient amount of drug on theballoon (3 microgram per square mm) was obtained. The inflated balloonwas folded, and then dried. The coated folded balloon was then rewrappedand sterilized for animal testing.

The coated PTCA balloon catheter was inserted into target site in theblood vessels (LAD, LCX and RCA) in the 25-45 ib pig was inflated to 12atm. The stretch ratio (the ratio of balloon diameter to vesseldiameter) was about 1.15-1.20. The drug was delivered into the targettissue in 30-60 seconds. The balloon catheter was then deflated and waswithdrawn from the animal body. The target blood vessel was harvested at0.25-24 hours after inflation. The drug content in the target tissue andthe residual drug remained on the balloon were analyzed by tissueextraction and HPLC. In some of the animal tests the stent was crimpedon the drug coated balloon catheters prior to deployment. In chronicanimal tests, angiography was performed before and after allinterventions and at 28-35 days after the procedure. Luminal diameterswere measured and late lumen loss was calculated. Late lumen loss is thedifference between the minimal lumen diameter measured after theintervention and minimal lumen diameter after a period of follow-uptime. Restenosis may be quantified by the diameter stenosis, which isthe difference between the mean lumen diameters at follow-up andimmediately after the procedure divided by the mean lumen diameterimmediately after the procedure.

The animal test results for the Formulation 18-28 are reported here. Alldata is the average of five or six experimental data points.

The drug content of the formulation 18 on the 3.5 mm balloon catheterswas 3.26 μg/mm². After the 15-30 minute procedure, the residual drug onthe balloon was 15.92 μg or 2.3% of the total drug loading. The drugcontent in the tissue harvested 15-30 minutes after the procedure was64.79 μg or 9.2% of the total drug content originally loaded on theballoon. If the 18 mm stent was depolyed by the coated balloon, theresidual drug on the balloon was 31.96 μg or 4.5% of the total drugload, and the drug content in tissue harvested 15-30 minutes after theprocedure was 96.49 μg, or 13.7% of drug load. The stretch ratio was 1.3in the procedure. The late lumen loss after 28-35 days was 0.10 (sd 0.2)mm. The diameter stenosis was 3.3%.

The drug content of the formulation 19 on the 3.5 mm balloon catheterswas 3.08 μg/mm². After the 15-30 minute procedure, the residual drug onthe balloon was 80.58 μg or 11.4% of the total drug load. The drugcontent in tissue harvested 15-30 minutes after the procedure was 42.23μg or 6.0% of the total drug load. After 28-35 days late lumen loss was0.30 (sd 0.23) mm. The diameter stenosis was 5.4%.

The drug content of formulation 20 on the 3.5 mm balloon catheters was3.61 μg/mm². After the 15-30 minute procedure, the residual drug on theballoon was 174.24 μg or 24.7% of the total drug load. The drug contentin tissue harvested 15-30 minutes after the procedure was 83.83 μg or11.9% of the total drug load. When deployed with a pre-crimped 18 mmstent, the residual drug on the balloon was 114.53 μg or 16.1% of thetotal drug load, and the drug content in the tissue harvested 15-30minutes post procedure was 147.95 μg or 18.1% of the total drug load.The stretch ratio was 1.3 in the procedure. Late lumen loss after 28-35days was 0.10 (sd 0.1) mm. The diameter stenosis was 3.4%.

The drug content of formulation 21 on the 3.5 mm balloon catheters was4.71 μg/mm². After the 15-30 minute procedure, the residual drug on theballoon was 44.39 μg or 6.3% of the total drug load. The drug content intissue harvested 15-30 minutes after the procedure was 77.87 μg or 11.0%of the total drug load. After 28-35 days minimal lumen diameter was 0.23(sd 0.44) mm. The diameter stenosis was 7.3%.

The drug content of formulation 22 on the 3.5 mm balloon catheters was3.85 μg/mm². After the 15-30 minute procedure, the residual drug on theballoon was 24.59 μg or 3.5% of the total drug load. The drug content intissue harvested 15-30 minutes after the procedure was 37.97 μg or 5.4%of the total drug load. After 28-35 days late lumen loss was 0.33 (sd0.14) mm. The diameter stenosis was 6.7%.

The drug content of formulation 23 on the 3.5 mm balloon catheters was3.75 μg/mm². After 60 minute procedure, the residual drug on the balloonwas 0.82 μg or 0.1% of the total drug load. The drug content in thetissue harvested 60 minutes after the procedure was 45.23 μg or 5.5% ofthe total drug load. After 28-35 days late lumen loss was 0.49 (sd 0.26)mm. The diameter stenosis was 11.3%.

The drug content of formulation 24 on the 3.5 mm balloon catheters was3.35 μg/mm². After the 60 minute procedure, the residual drug on theballoon is 62.07 μg and 7.5% of the total drug loading. The drug contentin the tissue harvested 60 minutes after the procedure was 40.55 μg or4.9% of the total drug load. After 28-35 days late lumen loss was 0.47(sd 0.33) mm. The diameter stenosis was 9.9%.

The drug content of formulation 25 on the 3.5 mm balloon catheters was3.41 μg/mm². After the 60 minute procedure, the residual drug on theballoon was 50.0 μg or 6.0% of the total drug load. The drug content inthe tissue harvested 60 minutes post procedure was 26.72 μg or 3.2% ofthe total drug load. After 28-35 days late lumen loss was 0.36 (sd 0.41)mm. The diameter stenosis was 9.3%.

The drug content of formulation 28 on the 3.5 mm balloon catheters was3.10 μg/mm². After the procedure, the residual drug on the balloon was1.9% of the total drug load. The drug content in tissue harvested 2hours after the procedure was 34.17 μg or 5.0% of the total drug load.In tissue harvested after the procedure, the drug content in tissue was28.92 μg or 4.2% of the total drug load.

The drug content of control formulation (uncoated balloon) on the 3.5 mmballoon catheters was 0.0 μg/mm². After the procedure, residual drug onthe balloon was 0% of the total drug load. The drug content in tissueharvested 15 minutes after the procedure was 0 μg. In tissue harvested24 hours after the procedure, the drug content in tissue was 0 μg. after28-35 days late lumen loss was 0.67 (sd 0.27) mm. The diameter stenosisis 20.8%. In the second repeat experiment, the stretch ratio was 1.3.The late lumen loss was 1.1 (sd 0.1). The diameter stenosis was 37.5%.

The drug content of formulation 26 on the 3.5 mm balloon catheters was3.21 μg/mm². After the 15-30 minute procedure, the residual drug on theballoon was 13.52 μg or 1.9% of the total drug loading. The drug contentin the tissue was 28.32 μg or 4.0% of the total drug load. When theballoon was deployed with a pre-crimped 18 mm stent, the residual drugon the balloon was 26.45 μg or 3.7% of the total drug load. The drugcontent in tissue was 113.79 μg or 16.1% of the total drug load. After28-35 days, late lumen loss was 0.27 (sd 0.15) mm. The diameter stenosiswas 7.1%.

The drug content of formulation 27 without additive on the 3.5 mmballoon catheters was 4.22 μg/mm². After the 15-30 minute procedure, theresidual drug on the balloon was 321.97 μg or 45.6% of the total drugload. The drug content in the tissue was 12.83 μg or 1.8% of the totaldrug load.

The drug absorption of the formulation 18-25 in the invention is higherthan those of formulation 26 and formulation 27. Late lumen loss after28-35 days follow up was improved.

Example 16

6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20 mm inlength) were inflated at 1-3 atm. The inflated balloon was loaded with aformulation 18-25 in example 1. The sufficient amount of drug on theballoon (3 μg/mm²) was obtained. The inflated balloon was dried. Thedrug coated balloon was then loaded with a top coating formulation. Thetop coating formulation in acetone or ethanol was chosen from gentisicacid, methyl paraben, acetic acid, Tween 80, Tween 20, vanillin andaspirin. The coated folded balloon was dried, then rewrapped andsterilized for animal testing.

A floating experiment was designed to test how much drug is lost duringballoon catheter insertion and transit to the target site prior toinflation. A control balloon catheter was coated with formulation 18.Top-coated catheters also were prepared having a top coating of propylparaben. For top-coated catheters, the balloon catheter was coated withformulation 18, then dried, 25-50 mg propyl paraben (about 50% ofpaclitaxel by weight) in acetone was coated over the formulation 18coating. Each of the control and top-coated balloon catheters wasinserted in pig arteries. The floating time in pig arterial vasculaturewas 1 minute. The drug, additive and top coating were released. Thecatheter was then withdrawn. The residual drug on the balloon catheterswas analyzed by HPLC. The residual drug content of the control ballooncatheters was 53% of the total drug loading. The residual drug contentof the top-coated balloon catheter was 88%. The top coat reduced drugloss in the vasculature during conditions that simulate transit of thedevice to a site of therapeutic intervention. The same animal tests wereperformed as in Example 15 with formulation 18 first coated on theballoon, and propyl paraben as a top coating layer overlying the firstcoating layer. The drug content on the 3.5 mm balloon catheter was 3.39μg/mm². After the procedure, residual drug on the balloon was 64.5 μg,or 8.6% of the total drug load. The drug content in the tissue was 28.42μg, or 4% of the total drug load.

Example 17

6 PTCA balloon components (3.5 and 3.0 mm in diameter and 20 mm inlength) were loaded with formulation 18 provided in Example 1. Asufficient amount of drug (3 μg/mm²) was obtained on the balloonsurface. The balloon was dried.

A formulation for a top coating layer was then prepared. The formulationof the top coating layer was paclitaxel, and one additive chosen fromTween 20, Tween 80, polypropylene glycol-425 (PPG-425), and polypropylglycol-1000 (PPG-1000), in acetone. The balloon surface of the controlcatheters was only loaded with formulation 18. 25-50 mg of the topcoating formulation (about 50% of paclitaxel by weight) in acetone wascoated over the formulation 18 coating layer on the other balloonsurfaces. The coated balloons were dried for drug releasing testing invitro.

The releasing experiment was designed to test how much drug is lostduring balloon inflation. Each of the coated balloons were inflated to12 atm. in 1% BSA solution at 37° C. for 2 minutes. The drug, additiveand top coating were released. The residual drug on the ballooncatheters was analyzed by HPLC. The residual drug content of the controlballoon catheter was 34% of the total drug loading. The residual drugcontent of of the balloon catheter that included a top coating layerwith Tween 20, Tween 80, polypropylene glycol-425 (PPG-425) orpolypropyl glycol-1000 (PPG-1000) was 47%, 56%, 71% and 81%,respectively. Thus, the top coating layer reduced drug loss in the testsin vitro during inflation of the balloon components.

1-79. (canceled)
 80. A balloon catheter comprising a coating layeroverlying an exterior surface of the balloon catheter, wherein: theballoon catheter is sized and configured for insertion into a passage ofa respiratory system; the coating layer comprises a water insoluble drugand a combination of a first additive and a second additive; the waterinsoluble drug is chosen from paclitaxel and rapamycin; the firstadditive is chosen from PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonooleate, or N-octanoyl N-methylglucamine; and the second additive ischosen from sorbitol, glucose, sucrose, lactobionic acid,gluconolactone, meglumine, lactic acid, gentisic acid, or combinationsthereof.
 81. The balloon catheter of claim 80, wherein: the firstadditive is PEG-20 sorbitan monolaurate; and the second additive issorbitol.
 82. The balloon catheter of claim 80, wherein: the drug ispaclitaxel; the first additive is PEG-20 sorbitan monolaurate; and thesecond additive is sorbitol.
 83. The balloon catheter of claim 80,wherein: the first additive is PEG-20 sorbitan monolaurate; and thesecond additive is gluconolactone.
 84. The balloon catheter of claim 80,wherein: the first additive is PEG-20 sorbitan monolaurate; and thesecond additive is lactobionic acid.
 85. The balloon catheter of claim80, wherein: the drug is paclitaxel; the first additive is PEG-20sorbitan monolaurate; and the second additive is gluconolactone.
 86. Theballoon catheter of claim 80, further comprising a top layer over thecoating layer.
 87. The balloon catheter of claim 80, further comprisingan adherent layer between the exterior surface and the coating layer.88. The balloon catheter of claim 87, wherein the adherent layer ischosen from polyolefins, polyisobutylene, ethylene-α-olefin copolymers,acrylic polymers and copolymers, polyvinyl chloride, polyvinyl methylether, polyvinylidene fluoride and polyvinylidene chloride,polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl acetate,ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, Nylon 12, polycaprolactone, polyoxymethylenes, polyethers,epoxy resins, polyurethanes, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, chitins,polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxidecopolymers, polyethylene glycol, polypropylene glycol, polyvinylalcohol, and mixtures thereof.
 89. The balloon catheter of claim 88,further comprising a top layer over the coating layer.
 90. A method fortreating a respiratory system, the method comprising: inserting into anairway a balloon catheter comprising a coating layer overlying anexterior surface of the balloon catheter, wherein: the coating layercomprises a drug, a first additive, and a second additive; the drug ischosen from paclitaxel and rapamycin, the first additive is chosen fromPEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, or N-octanoylN-methylglucamine; and the second additive is chosen from sorbitol,glucose, sucrose, lactobionic acid, gluconolactone, meglumine, lacticacid, gentisic acid, or combinations thereof; inflating the ballooncatheter and releasing the drug to a wall of the airway; deflating theballoon; and withdrawing the balloon catheter from the airway.
 91. Themethod according to claim 90, wherein: the first additive is PEG-20sorbitan monolaurate; and the second additive is sorbitol.
 92. Themethod according to claim 90, wherein: the drug is paclitaxel; the firstadditive is PEG-20 sorbitan monolaurate; and the second additive issorbitol.
 93. The method according to claim 90, wherein: the firstadditive is PEG-20 sorbitan monolaurate; and the second additive isgluconolactone.
 94. The method according to claim 90, wherein: the firstadditive is PEG-20 sorbitan monolaurate; and the second additive islactobionic acid.
 95. The method according to claim 90, wherein: thedrug is paclitaxel; the first additive is PEG-20 sorbitan monolaurate;and the second additive is gluconolactone.
 96. The method according toclaim 90, wherein the balloon catheter further comprises a top layerover the coating layer.
 97. The method according to claim 90, whereinthe balloon catheter further comprises an adherent layer between theexterior surface and the coating layer.
 98. The method according toclaim 97, wherein the adherent layer is chosen from polyolefins,polyisobutylene, ethylene-α-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, Nylon 12,polycaprolactone, polyoxymethylenes, polyethers, epoxy resins,polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulosebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, carboxymethyl cellulose, chitins, polylactic acid, polyglycolicacid, polylactic acid-polyethylene oxide copolymers, polyethyleneglycol, polypropylene glycol, polyvinyl alcohol, and mixtures thereof.99. The method according to claim 98, wherein the balloon catheterfurther comprises a top layer over the coating layer.